Paracetamol: overdose-induced oxidative stress

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Drug Metabolism Reviews

ISSN: 0360-2532 (Print) 1097-9883 (Online) Journal homepage: http://www.tandfonline.com/loi/idmr20

Paracetamol: overdose-induced oxidative stress toxicity, metabolism, and protective effects of various compounds in vivo and in vitro Xu Wang, Qinghua Wu, Aimei Liu, Arturo Anadón, José-Luis Rodríguez, María-Rosa Martínez-Larrañaga, Zonghui Yuan & María-Aránzazu Martínez To cite this article: Xu Wang, Qinghua Wu, Aimei Liu, Arturo Anadón, José-Luis Rodríguez, María-Rosa Martínez-Larrañaga, Zonghui Yuan & María-Aránzazu Martínez (2017) Paracetamol: overdose-induced oxidative stress toxicity, metabolism, and protective effects of various compounds in�vivo�and�in�vitro, Drug Metabolism Reviews, 49:4, 395-437, DOI: 10.1080/03602532.2017.1354014 To link to this article: https://doi.org/10.1080/03602532.2017.1354014

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DRUG METABOLISM REVIEWS, 2017 VOL. 49, NO. 4, 395–437 https://doi.org/10.1080/03602532.2017.1354014

REVIEW ARTICLE

Paracetamol: overdose-induced oxidative stress toxicity, metabolism, and protective effects of various compounds in vivo and in vitro na, Jose -Luis Rodrıgueza, Xu Wanga,b, Qinghua Wuc,d, Aimei Liub, Arturo Anado a b,e,f ~aga , Zonghui Yuan Marıa-Rosa Martınez-Larran and Marıa-Aranzazu Martıneza a

Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, Spain; National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, China; cCollege of Life Science, Yangtze University, Jingzhou, China; d Faculty of Informatics and Management, Center for Basic and Applied Research, University of Hradec Kralove, Hradec Kralove, Czech Republic; eMAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, China; fHubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China b

ABSTRACT

ARTICLE HISTORY

Paracetamol (APAP) is one of the most widely used and popular over-the-counter analgesic and antipyretic drugs in the world when used at therapeutic doses. APAP overdose can cause severe liver injury, liver necrosis and kidney damage in human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with APAP, and various antioxidants were evaluated to investigate their protective roles against APAP-induced liver and kidney toxicities. To date, almost no review has addressed the APAP toxicity in relation to oxidative stress. This review updates the research conducted over the past decades into the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and oxidative stress as a result of APAP treatments, and ultimately their correlation with the toxicity and metabolism of APAP. The metabolism of APAP involves various CYP450 enzymes, through which oxidative stress might occur, and such metabolic factors are reviewed within. The therapeutics of a variety of compounds against APAP-induced organ damage based on their anti-oxidative effects is also discussed, in order to further understand the role of oxidative stress in APAP-induced toxicity. This review will throw new light on the critical roles of oxidative stress in APAP-induced toxicity, as well as on the contradictions and blind spots that still exist in the understanding of APAP toxicity, the cellular effects in terms of organ injury and cell signaling pathways, and finally strategies to help remedy such against oxidative damage.

Received 24 March 2017 Accepted 5 July 2017

Introduction Paracetamol, also called acetaminophen or 4-hydroxyacetanilide or N-acetyl-para-aminophenol (APAP), being a non-steroidal anti-inflammatory drug (NSAID), was first synthesized in 1878 by Morse (Figure 1) and first used clinically by von Mering in 1887 (Bertolini et al. 2006). APAP is one of the most widely and popular used over-the-counter (OTC) analgesic and antipyretic drugs in the world (Ferah et al. 2013; Pu et al. 2016). Usually, APAP has a reasonable safety profile when consumed in therapeutic doses. APAP does not produce gastrointestinal damage or untoward cardiorenal effects (Bertolini et al. 2006), and is contained in many preparations. Due to its wide availability and comparably higher toxicity than ibuprofen and aspirin, there is a higher potential for its overdose (Sheen et al. 2002). It is

KEYWORDS

Paracetamol; ROS; RNS; oxidative stress; toxicology; mechanism

reported that a 150 mg/kg b.w. dose of APAP has a high probability of toxic effects (Dart et al. 2006). Concerning the doses of APAP that can induce toxicity in human, it should be worthwhile to distinguish acute single administrations from repeated supra-therapeutic doses, and also to mention that some individuals are susceptible to hepatotoxicity at therapeutic doses (Amar and Schiff 2007; O'Connell and Watkins 2010; Winnike et al. 2010). Overdosing with APAP is the leading cause of hospital admission for hepatotoxicity, acute liver failure (Ferah et al. 2013), and renal damage (Placke et al. 1987; Abdul Hamid et al. 2012). APAP toxicity is one of the major causes of poisoning worldwide, including the USA and Great Britain (Gunnell et al. 2000; Lee 2008; Ferah et al. 2013). According to United States statistics, more than 100,000 cases of APAP poisoning occur

CONTACT Arturo Anadon [email protected] Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense [email protected] National Reference Laboratory of Veterinary Drug Residues (HZAU) de Madrid, 28040 Madrid, Spain; Zonghui Yuan and MAO Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, Hubei 430070, China ß 2017 Informa UK Limited, trading as Taylor & Francis Group

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X. WANG ET AL.

Figure 1. Chemical structure of paracetamol (APAP).

annually (Oliver and Lewis 2010). In 2008, according to the American Association of Poison Control Centers, APAP overdose occurred in 27,790 cases, resulting in 13,650 hospitalizations and 43 deaths (Ferah et al. 2013). APAP causes a fatal hepatic necrosis and hepatic failure in overdose along with oxidative stress such as lipid, DNA and protein peroxidation, significant decrease in hepatic GSH (reduced glutathione (GSH)) levels, and alteration in the antioxidant enzyme system (Ramachandra Setty et al. 2007; Jothy et al. 2012; Simeonova et al. 2013; Hohmann et al. 2015), decrease in the activity of hepatic d-aminolevulinic acid dehydratase (d-ALA-D) (Rocha et al. 2005), and an increase in the various inflammatory cytokines (Galal et al. 2012; Somanawat et al. 2013; Polat et al. 2015). Although nephrotoxicity is less common than hepatotoxicity in APAP overdose, renal tubular damage and acute renal failure can occur even in the absence of liver injury (Jones and Vale 1993), and can even lead to death in humans and experimental animals (Naggayi et al. 2015). Furthermore, people with compromised kidney function can develop NSAID toxicity even at normal NSAID dosages (Whelton and Hamilton 1991). Additionally, APAP use represents a putative risk factor for the development of asthma because there is convincing epidemiological evidence that the risk of asthma may be increased with exposure to APAP in the intrauterine environment, infancy, later childhood, and adult life (Farquhar et al. 2010). Inadequate antioxidant defense or overproduction of free radicals usually leads to oxidative stress, which may be initiated by reactive oxygen species (ROS), such as the hydroxyl radical (HO), superoxide anion (O 2 ), and perhydroxy radical (HOO), and by reactive nitrogen species (RNS) including nitric oxide (NO) and peroxynitrite (ONOO) (Dasuri et al. 2013; Adams et al. 2015; Swomley and Butterfield 2015; Wang et al. 2016a). Oxidative stress, ROS, and RNS are suggested to play important roles in the induction of APAP-induced damage to lipids, DNA and proteins in human beings and animals. During the metabolism of APAP, the highly

toxic APAP metabolite N-acetyl-p-benzoquinone-imine (NAPQI) was generated, and even at low dosages, the amount of NAPQI formed got conjugated to the hepatic reduced GSH store (Das et al. 2011). In case of APAP overdose or in conditions when the hepatic GSH store is depleted, NAPQI could react further with cellular proteins causing oxidative stress, lipid peroxidation, and excessive free radicals. In this context, the influence of oxidative stress, ROS, and RNS on APAP-associated hepatotoxicity and nephrotoxicity has been investigated (Jamil et al. 1999; Arafa 2009; Perez et al. 2011; Abdul Hamid et al. 2012; Kisaoglu et al. 2014; Naggayi et al. 2015). Various studies in cells (Table 1) and animals such as human beings (Table 2), rabbits, rats, and mice (Table 3), have identified that oxidative stress plays a critical role in the toxic effects induced by APAP. To date, several reviews on APAP have been published, including those that have focused on the following: Comparative efficacy of ibuprofen and APAP and pharmacology of APAP (Moore et al. 2015), pharmacology of APAP (Graham et al. 2013), oxidative stress during APAP hepatotoxicity (Jaeschke et al. 2003; Du et al. 2016), and toxicity of APAP (Jaeschke et al. 2012). Jaeschke et al. (2012) had reviewed the critical role of mitochondria damage in the liver injury induced by APAP as well as oxidative stress generated from mitochondria injury. In recent years, toxicity, toxic mechanisms, and the antagonistic effects on hepatotoxicity and renal toxicity induced by APAP have attracted more and more attention, and some new articles about the important role of oxidative stress and antioxidants used as antagonists in the toxicities of APAP have been published. Therefore, it is appropriate at this point to review the recent progress into research focused on the toxic mechanism of APAP and the studies of testing antioxidant compounds to limit or reverse APAP-induced oxidative stress and/or toxicity. The scope of this review is primarily intended to summarize the evidence associated with APAP-induced toxicity related to oxidative stress, and therefore to find considerable potential therapeutics for toxicity induced by APAP overdose. The studies related to the toxicity of APAP and oxidative stress, in in vitro and in vivo conditions are summarized in Tables 1–3, respectively. Furthermore, the metabolic pathways, metabolizing enzymes, the influential factors in the metabolism of APAP, and the toxicity of its metabolites are also reviewed. This review collates evidence reported over the past 20 years, which indicates that levels of oxidative stress, ROS or RNS generation, and antioxidase might correlate closely with hepatotoxicity and renal toxicity resulting from APAP. Furthermore, information on the metabolism of APAP and various antioxidants used as antagonists are also

24 h

1, 3, 5, 6, 12, 24, and 48 h

22 h

Rat embryonic liver cells (RLC-18 cells)

Hepa 1–6 mouse hepatoma cells, and Rho cells

Primary monolayer cultures of rat hepatocytes

Dose

APAP (0.00001, 0.0001, 0.001, 0.01, and 0.1 mM)

APAP (12 mM)þSSE (100 mg/mL culture medium)

APAP (0.05, 0.1, and 0.3 mM)

APAP (6 and 15 mM)

APAP (0.1 mM)þsaponarin (60–0.006 mg/mL)

APAP (7 mM)þDSE (0.06–1 mg/ mL)

Aim

The effects of APAP on reactive oxygen and reactive nitrogen intermediate production

The effect of mtDNA depletion on changes in ABC transporter protein expression in response to bile acids and APAP The hepatoprotective effects of SSE against APAP-induced liver injury

The embryonal and developmental toxicity of APAP

The protective effects of DSE and its major phenolic acid components against CYP2E1-mediated APAPinduced hepatic toxicity The hepatoprotective efficacy of saponarinin APAPinduced liver toxicity

Result/conclusion DSE: decreased APAP-induced total GSH depletion and preserved redox status (GSH/GSSG ratio) in hepatocytes. APAP: decreased levels of cellular GSH, and elevated MDA quantity. Saponarin: ameliorated APAP-induced hepatotoxicity by the restored MDA quantity and GSH levels in a concentration-dependent manner. APAP: significantly decreased GSH levels and enhanced telomerase activity. APAP: increased ROS generation by mitochondria, gene expression of Mrp1, Mrp4, Shp, and Nrf2 in Hepa 1-6 mouse hepatoma cells. APAP: reduced GSH by almost 80%, while most of the SSE in general offered relatively good protection. APAP: increased H2O2 and O 2 production, and caused a significant decrease in NO generation.

References

Jamil et al. (1999)

Reen et al. (2001)

Perez et al. (2011)

Bader et al. (2011)

Simeonova et al. (2013)

Zhou et al. (2015a)

APAP: paracetamol; DSE: Danshen (Salvia miltiorrhiza) water extract; GSH: reduced glutathione; GSSG: oxidized glutathione; MDA: malondialdehyde; Mrp: multidrug resistance associated protein; NO: nitric oxide; Nrf2: nuclear factor E2-related factor 2; ROS: reactive oxygen species; Shp: small heterodimer partner; SSE: Swertia species extract.

0.5, 20, 24, 40, 60, 80, 100, and 120 h

1h

Rat hepatocytes

U937 cells

24 h

Time of incubation

Primary rat hepatocytes

Cell type

Table 1. In vitro Paracetamol (APAP)-related oxidative stress studies.

DRUG METABOLISM REVIEWS 397

398

X. WANG ET AL.

Table 2. Paracetamol (APAP) related oxidative stress studies in human being. Species

Time of exposure

Dose

Aim

Result/conclusion

Reference

Human beings

14 days

APAP (3000 mg/day, orally)þsulfur amino acid intake (37 mg/kg b.w./day, orally) at the end of 14day period of APAP treatment vs. before the treatment

Evaluate how older persons (aged >69 years) satisfy the extra demand in sulfur amino acids induced by long-term APAP treatment

Pujos-Guillot et al. (2012)

Children

3–10 days

APAP (30–75, and 80–180 mg/kg b.w./day) orally

Examine GSH and antioxidant status changes from febrile children (aged 2 months to 10 years) receiving APAP

Men and women

14 days

APAP (1000 mg 4 times a day, for 14 days) orally

Determine whether regular intake of maximum therapeutic doses of APAP reduced serum antioxidant capacity in healthy volunteers (aged 19–32 years

APAP treatment: decreased antioxidative defenses, no effects on blood concentration of total (reduced and oxidized) GSH, plasma total free cysteine, sulfates, and amino acid profile. The increase in dietary intake of proteins and the analysis of urinary APAP conjugates suggest an induced pro-oxidant status. APAP: decreased the mean total antioxidant capacity, and no effect on urea, creatinine, uric acid, ALT, ALP, and GGT. APAP (80–180 mg/kg b.w./day): increased AST activity and reduced antioxidant status (decrease of GST, SOD and GR activity, and erythrocyte GSH concentrations) Serum APAP concentration: 5.25 ± 0.70 mg/L at 1-h post-dosing and 7.14 ± 0.66 mg/L on day 14 (chronic dosing). Chronic ingestion of maximum therapeutic doses of APAP: caused a gradual decrease in serum antioxidant capacity reaching significance on day14, possibly by a reduction in GSH.

Kozer et al. (2003)

Nuttall et al. (2003)

ALP: alkaline phosphatase; ALT: alanine aminotransferase; APAP: paracetamol; AST: aspartate aminotransferase; GGT: gamma glutamyl transferase; GR: glutathione reductase; GSH: reduced glutathione; SOD: superoxide dismutase.

summarized with a view to probing effective strategies for the application of antioxidants to inhibit APAPinduced toxicity.

Oxidative stress and toxicity Generation of oxidative stress, ROS, and RNS APAP may induce ROS and decrease RNS generation in in vitro models. In U937 cells, it was noted that APAP could increase H2O2 and O 2 production and result in oxidative stress after the treatment of APAP at (0.01–100 mM), whereas APAP (0.01–10 mM) caused a significant decrease in NO generation (Jamil et al. 1999). Another study revealed that after exposure of Hepa 1–6 mouse hepatoma cells to APAP (50, 100, and 300 mM), of APAP increased ROS generation by mitochondria (Perez et al. 2011). Similarly, ROS generation was noted in the in vivo model to investigate liver damage induced by APAP. It was documented that APAP (200 mg/kg b.w.) significantly increased hepatic H2O2 levels in C57BL/6J mice, indicating that APAP could lead to ROS production in APAP-induced hepatic toxicity (Pu et al. 2016). Once administration of APAP (3 g/kg b.w.) was reported to induce liver hydroperoxides (Firdous et al. 2011).

Contrary to the decrease in the NO generation in in vitro models such as U937 cells, several in vivo studies suggested that APAP significantly increased NO production. Arafa (2009) reported that APAP increased hepatic NO content when male rats were treated with APAP (1 g/kg b.w.) for 10 consecutive days. In the studies to reveal the liver damage induced by APAP, liver or serum NO levels were significantly increased when rats were exposed to APAP (1, 2, or 3 g/kg b.w.) once (Madkour and Abdel-Daim 2013; Kisaoglu et al. 2014; El Morsy and Kamel 2015). The study carried by James et al. (2003) revealed that APAP did not cause hepatic lipid peroxidation in wild-type mice but did cause lipid peroxidation in iNOS knockout mice, suggesting that NO generation may play a role in controlling lipid peroxidation and that reactive nitrogen/oxygen species may be important in APAP toxicity. A recent study showed that after exposure of mice to APAP (250 mg/kg b.w./day) for 7 days, APAP resulted in liver damage followed by apparently increased hepatic NO levels (Mohamad et al. 2015). The results of these studies indicate that the generation of ROS and RNS play important roles in the oxidative stress and related toxicities induced by APAP. However, the decrease of NO in in vitro and of its

APAP (once) after ALE (14 days)

APAP (once) after LB (7 days) or NAC (once) or first LB (7 days), second APAP (once), third NAC (once)

APAP (once) after FG, FRG or silymarin (8 days)

APAP (once) after aliskiren

Male Wistar rats

Male Wistar rats

Male Wistar rats

APAP (once) after AEAP (14 days)

APAP after carvedilol, prazosin, metoprolol and prazosin plus metoprolol for 9 days

Time of exposure

Male Sprague–Dawley rats

Rats Male Sprague–Dawley rats

Rabbits Male rabbits

Species

Examine the protective effect of ALE against APAPinduced liver injury

or APAP (1000 mg/kg b.w.) Evaluate the hepatoprotective orally þ LB (100 mg/kg b.w.) Ip, or and antioxidant effects of APAP (1000 mg/kg b.w.) LB extract against APAPorally þ NAC (1500 mg/kg b.w.) Ip, induced liver injury or APAP (1000 mg/kg b.w.) orally þ LB (100 mg/kg b.w.) Ip and NAC (1500 mg/kg b.w.) Ip APAP (500 mg/kg b.w.) Ip þ FG Assess the hepato-protective (50 mg/kg b.w.), or APAP (500 mg/ effects of FG and FRG kg b.w.) Ip þ FRG (50 mg/kg b.w.) against APAP-induced orally, or APAP (500 mg/kg b.w.) hepatotoxicity Ip þ silymarin (100 mg/kg b.w.) orally APAP (2000 mg/kg b.w.) oralEstablish the relationship ly þ aliskiren (50 and 100 mg/ between hepatotoxicity and kg b.w.) orally the RAAS by examining APAP-induced hepatotoxicity

APAP (2000 mg/kg b.w.), orally þ ALE (1500 mg/kg b.w.), or APAP (2000 mg/kg b.w.), orally þ NAC (100 mg/kg b.w.), orally

APAP: decreased liver SOD activity and GSH levels, and increased MDA levels, and TNF-a and TGF-b gene expressions. Aliskiren: increased liver SOD activity and GSH levels, and decreased liver MDA levels, TNF-a and TGF-b gene expression.

APAP: induce JNK- and GST-related genes in its hepatotoxicity. FG: hepatoprotective activity against APAP-induced liver injury better than FRG.

APAP: increased the serum AST, ALT, ALP, LDH, total bilirubin, triglycerides and cholesterol and decreased total protein levels. AEAP: attenuated the APAP-induced liver damage, due to its potent antioxidant activity. APAP: increased levels of serum amino-transferases, induced liver cell apoptosis, increased liver MDA and NO levels, decreased liver GSH content, GR, GST, and SOD activities. Pretreatment with ALE: replenished hepatic GSH, reversed oxidative stress parameters, DNA damage, and necrosis induced by APAP. APAP: increased TOS and OSI values, serum ALT, AST, and decreased the serum TAS level. LB: significantly increased the TAS level and decreased TOS and OSI levels.

Result/conclusion

APAP (2000 mg/kg b.w.) orally þ AEAP Examine the protective effect (250 and 500 mg/kg b.w.) orally of AEAP against APAPinduced liver toxicity

Aim APAP: increased AST, ALT, ALP, total bilirubin, MDA level in serum and in liver homogenate, decreased GSH activity, and resulted in severe hepatotoxicity. Prior treatment with prazosin: returned MDA and GSH level induced by APAP back to the control value. Carvedilol and prazosin plus metoprolol treatments: decreased MDA in serum and liver homogenate.

Dose APAP (1000 mg/kg b.w.) oralEvaluate the hepatoprotective ly þ carvedilol (10 mg/kg b.w.) potential of carvedilol, praorally, or APAP (1000 mg/kg b.w.) zosin, metoprolol and praorally þ prazosin (0.5 mg/kg b.w.) zosin plus metoprolol in orally, or APAP (1000 mg/kg b.w.) APAP-induced orally þ metoprolol (10 mg/kg b.w.) hepatotoxicity orally, or APAP (1000 mg/kg b.w.) orally þ combination of metoprolol (10 mg/kg b.w.) and prazosin (0.5 mg/kg b.w.) orally

Table 3. Paracetamol (APAP) related oxidative stress studies in animals.

(continued)

Karcioglu et al. (2015)

Igami et al. (2015)

G€ und€ uz et al. (2015)

El Morsy and Kamel (2015)

Chellappan et al. (2016)

Zubairi et al. (2014)

Reference

DRUG METABOLISM REVIEWS 399

Six weeks of RGDS before APAP (once) APAP (once), before CPE (500 and 750 mg/kg b.w.) for 7 days APAP (once) before leptin

APAP once after MECCF (7 days) APAP (once), and TPP or NAC (given 1h later APAP)

APAP (twice) after NSE (7 days) Co-administration of APAP and drugs (8 weeks)

Male Sprague–Dawley rats

Male Wistar rats

Female Wistar rats

Male Wistar rats

Male Wistar rats

Male Wistar rats

Male Sprague–Dawley rats

Time of exposure APAP (every 72 h for 10 days) along with DRDC/AY/8060 (10 days)

Male Wistar rats

Species

Table 3. Continued Dose

APAP (100 mg/kg b.w.) þ 7-hydroxy40 ,5,6-trimethoxy-isoflavone (100 mg/kg b.w./week) orally, or APAP (100 mg/kg b.w.) þ 7hydroxy-5,6-dimethoxy-20 ,30 -methylenedioxyisoflavone (100 mg/ kg b.w./week) orally, or APAP (100 mg/kg b.w.) þ 5,6-dimethoxy20 ,30 -methylenedioxy-7-C-b-D-glucopyranosyl-isoflavone (100 mg/ kg b.w./week) orally

APAP (3000 mg/kg b.w.) orally þ NSE (250 and 500 mg/kg b.w.) orally

APAP (1000 mg/kg b.w.) orally þ TPP (20 mg/kg b.w.) Ip, or APAP (1000 mg/kg b.w.) orally þ thiamin (20 mg/kg b.w.) Ip, or APAP (1000 mg/kg b.w.) orally þ NAC (300 mg/kg b.w.) Ip

APAP (2000 mg/kg b.w.)þMECCF (300 mg/kg b.w.), orally

APAP (2000 mg/kg b.w.)þleptin (10 and 20 mg/kg b.w.) Ip

APAP (1000 mg/kg b.w.), orally þ CPE (500 and 750 mg/kg b.w.) orally

APAP (750 mg/kg b.w.) orally þ RGDS (5, 10, and 20% diet)

APAP (750 mg/kg b.w.), orally or Dgalactosamine (400 mg/kg b.w.) Ip þ DRDC/AY/8060 (120 and 240 mg/kg b.w.) orally

Aim

Result/conclusion

APAP: induced liver damage. RGDS: decreased MDA levels, and increased the activities of GSH, SOD, and CAT in liver. APAP: increased serum creatinine, uric acid and urea concentrations. CPE: ameliorated the effects of APAP.

APAP: increased liver MDA levels and decreased liver GSH levels. DRDC/AY/8060: reduced liver MDA levels and elevated GSH levels.

APAP: decreased serum GSH levels, increased serum TNF-a and MDA levels. Leptin prevented this damage due to its antioxidant and anti-inflammatory efficacy. The antioxidant and hepatoAPAP: decreased CAT and SOD activprotective activity of MECCF ity, and increased MDA levels, against APAP-induced while MECCF protected against toxicity them. Evaluate the effect of TPP, NAC APAP: decreased GPx, GST, SOD, GR and thiamin on oxidative and CAT activities in liver, and liver damage induced in increased liver MDA levels and NO rats by high-dose of APAP production. TPP, NAC, or thiamin with APAP: decreased liver MDA levels and NO generation, and prevented a decrease in enzymatic and nonenzymatic antioxidants such as GSH, GPx, GST, SOD, and CAT in the rat liver. Examine the effect of NSE on APAP: decreased liver GSH levels. acute liver damage induced NSE: significantly prevented the by APAP decrease in GSH levels. Evaluate the hepatoprotective APAP: reduced plasma TAC and liver and antioxidant effects of SOD, GPx, CAT, GST, and GSH new isoflavonoid in APAPactivities, and increased liver MDA induced liver damage levels. The three compounds of isoflavonoids: reversed the indexes mentioned above.

Assess the nephroprotective and ameliorative effects of CPE in APAP-induced nephrotoxicity Examine the hepatoprotective effects of leptin against APAP-induced liver injury

Evaluate the hepato-protective effects of DRDC/AY/8060 against APAP and D-galactosamine-induced hepatotoxicity Examine the effect of RGDS on liver damage induced by APAP

Reference

(continued)

Sakran et al. (2014)

Kushwah et al. (2014)

Kisaoglu et al. (2014)

Vakiloddin et al. (2015)

Polat et al. (2015)

Naggayi et al. (2015)

Madi Almajwal and Farouk Elsadek 2015)

Khan et al. (2015)

400 X. WANG ET AL.

APAP (once), agomelatine and NAC (given 1 h later APAP) APAP (once) after DS (7 days) or silymarin (7 days)

APAP (once) before HAREX (8 days) or silymarin (8 days)

APAP and MEFR (7 days)

Male Wistar rats

Male Wistar rats

Male and Female Wistar rats

Male Wistar rats

Evaluate the antioxidative burst and hepatoprotective effects of HAREX against APAP-induced liver injury

Examine the hepatoprotective effects of MEFR against APAP-induced liver injury

APAP (2000 mg/kg b.w.)þHAREX (200, 400, and 600 mg/kg b.w.), orally or APAP (2000 mg/ kg b.w.)þsilymarin (100 mg/ kg b.w.) orally

APAP (200 mg/kg b.w.), orally þ MEFR (100, 200, and 300 mg/kg b.w.) orally

APAP (2000 mg/kg b.w.)þagomelatine Evaluate the hepatoprotective (20 and 40 mg/kg b.w.) orally, or effects of agomelatine APAP (2000 mg/kg b.w.)þNAC against APAP-induced (140 mg/kg b.w.) orally hepatotoxicity APAP (3000 mg/kg b.w.), orally þ DS Examine the effect of DS on (500 and 1000 mg/kg b.w.) orally, liver damage induced by or APAP (3000 mg/kg b.w.)þsilyAPAP marin (200 mg/kg b.w.) orally

APAP (2000 mg/kg b.w.) orally þ infliximab (3, 5, and 7 mg/ kg b.w.) Ip or APAP (2000 mg/ kg b.w.) orally þ NAC (140 mg/ kg b.w.) orally

Drugs given twice (1 h before and 12 h after APAP)

Investigate whether the selective inhibition of PDE-5, and nonselective inhibition of PDE isozymes ameliorate hepatic toxicity induced by APAP The hepatoprotective activity of infliximab on APAPinduced hepatotoxicity

Male Wistar rats

Male Wistar rats

Examine the protection of bosentan against APAPinduced toxicity

NAC (twice) 12 h after APAP, or APAP (2000 mg/kg b.w.) orally þ NAC bosentan (once) before (140 mg/kg b.w., twice) orally, or APAP APAP (2000 mg/kg b.w.) orally þ bosentan (45 and 90 mg/ kg b.w.) orally APAP before SIL or AMP APAP (250 mg/kg b.w.) Ip þ SIL (7 days) (10 mg/kg b.w.) orally, or APAP (250 mg/kg b.w.) Ip þ AMP (10 mg/ kg b.w.) orally

Female Sprague–Dawley rats

Aim Assess the hepatoprotective efficacy of RIRA in APAPinduced liver toxicity

Dose APAP (2000 mg/kg b.w.) orally þ RIRA (200 and 400 mg/kg b.w.) orally

Time of exposure APAP (once), before RIRA (14 days)

Male Wistar rats

Species

Table 3. Continued Result/conclusion

Reference

APAP: increased serum TNF-a level and liver MDA content, and decreased SOD activity and GSH levels in liver. Infliximab or NAC: reduced serum TNF-a level, restored GSH, SOD and decreased MDA levels in liver. APAP: increased TNF-a and IL-6, and decreased SOD and GSH activities. NAC or agomelatine: reversed the changes induced by APAP. APAP: increased serum AST, ALT, ALP, MDA, and NO production, and decreased serum SOD and TAC activities. DS: reversed the changes induced by APAP. APAP: induced liver injury including decrease in total protein, albumin, SOD, CAT, GPx, GSH, and increase in total bilirubin, AST, ALT, ALP, total cholesterol. HAREX: reduced oxidative burst activity in whole blood, neutrophils (intra- and extra-cellular) and macrophages. HAREX: increased the serum levels of SOD, CAT, GPx and GSH. APAP: increased SGOT, and SGPT, and induced TBARS and GSH levels in the liver. MEFR: reversed TBARS and GSH levels induced by APAP.

(continued)

Parameswari et al. (2013)

Okokon et al. (2013)

Madkour and Abdel-Daim 2013)

Karakus et al. (2013)

Ferah et al. (2013)

RIRA (400 mg/kg b.w.): showed an Senthilkumar et al. elevation of SOD, CAT, GPx, GSH, 2014) improved the biochemical parameters (ALP, SGOT, and SGPT) and reversed toxic effects on erythrocytes and leucocytes. APAP: decreased SOD activity, GSH Yayla et al. (2014) levels and increased levels of MDA in the liver. Bosentan: improved the parameters mentioned above. SIL or AMP: attenuated APAP-induced Ekor et al. (2013) liver toxicity, reduced MDA levels, and increased GSH levels in the APAP-treated rats.

DRUG METABOLISM REVIEWS 401

APAP (once on day 7) 90 min before saponarin (7 days) or silymarin (7 days)

APAP and ZZR concurrent (7 days)

APAP (once) after honey (7 days) or silymarin (7 days)

APAP once, on the 14th day after MEAC (14 days) or silymarin (14 days)

APAP (once) after CMZ (7 days) or silymarin (7 days)

Male Wistar rats

Male Sprague–Dawley rats

Male Wistar rats

Female Wistar rats

Male Wistar rats

Time of exposure APAP (once) after AAb (7 days) or AAep (7 days)

Sprague–Dawley rats

Species

Table 3. Continued

Assess the effects of ZZR on APAP-induced nephrotoxicity

APAP (750 mg/kg b.w.) orally þ ZZR (200 and 400 mg/kg b.w.) Ip

APAP (3000 mg/kg b.w.) orally þ CMZ (50, 100, and 250 mg/kg b.w.) Ip, or APAP (3000 mg/kg b.w.) orally þ silymarin (100 mg/kg b.w.) orally

Evaluate the hepatoprotective activity of CMZ on APAPinduced hepatotoxicity

APAP (3000 mg/kg b.w.) Assess the hepatoprotective orally þ MEAC (200 and 400 mg/ effect of MEAC on APAPkg b.w.) orally, or APAP (3000 mg/ induced liver damage kg b.w.) orally þ silymarin (100 mg/ kg b.w.) orally

Evaluate the protective effect of honey against APAPinduced hepatotoxicity

Examine the hepato-protective efficacy of saponarin in APAP-induced liver toxicity

APAP (600 mg/kg b.w.) Ip þ saponarin (80 mg/kg b.w.) orally, or APAP (600 mg/kg b.w.) Ip þ silymarin (100 mg/kg b.w.) orally

APAP (2000 mg/kg b.w.). orally þ silymarin (100 mg/kg b.w.) orally, or APAP (2000 mg/ kg b.w.)þhoney (5, 10, and 20 g/ kg b.w.) orally

Aim Evaluate the antioxidant and hepatoprotective and antidiabetic efficacy of Acacia auriculiformis by its bark and empty pods

Dose APAP (2000 mg/kg b.w.), orally þ AAb (200 and 400 mg/kg b.w.) orally, or APAP (2000 mg/kg b.w.) orally þ AAep (100 and 200 mg/ kg b.w.) orally

Result/conclusion APAP: increased ALT, AST, ALP, MDA, and decreased SOD, CAT, GSH, and Gpx AAb and Aaep: restored the liver function markers (ALT, AST, and ALP) and hepatic antioxidants (SOD, CAT, GSH, and GPx) to the normal levels. APAP: increased MDA content and decreased GSH levels and antioxidant defense system in liver. Saponarin pretreatment: increase in antioxidant defense system and GSH levels and a decrease in MDA levels. APAP: decreased body weight and kidney weight, plasma GSH, SOD, and renal GSH levels, increased plasma creatinine, protein and MDA, renal MDA and AOPP. ZZR: prevented APAP-induced nephro-toxicity and oxidative impairments of the kidney. ZZR: reduced levels of plasma creatine, plasma and renal MDA, plasma protein carbonyl and renal AOPP. ZZR: increased plasma and renal GSH levels and plasma SOD activity. APAP: increased liver MDA levels, serum and liver IL-1b, serum ALT, AST, and decreased liver GSH content, GPx activity. Honey or silymarin: reduced ALT, AST, oxidative stress, and inflammatory cytokines. APAP: increased serum ALT, AST, total bilirubin, liver MDA levels and decreased serum albumin, liver weight, liver GSH, CAT, and total thiol levels. MEAC: decreased MDA levels, and increased GSH, CAT and total thiol levels. APAP: increased SGOT, SGPT, ALP, bilirubin, liver TBARS levels, and liver hydroperoxides. CMZ: reversed these changes induced by APAP, and decreased both TBARS levels and hydroperoxides in liver induced by APAP.

Reference

(continued)

Firdous et al. (2011)

Ashok Kumar et al. (2011)

Galal et al. (2012)

Abdul Hamid et al. (2012)

Simeonova et al. (2013)

Sathya and Siddhuraju (2013)

402 X. WANG ET AL.

APAP and EESM or silymarin once daily (10 days)

APAP (once on day 7) and PdAE or PdEE (9 days)

APAP (once, 1 h after EEAFA) or silymarin (on day 10), and EEAFA (10 days) or silymarin (10 days)

APAP (once) 1 h after purslane or vitamin C (on day 14) and purslane (14 days)

APAP (once) before CL (7 days)

Male Wistar rats

Male and female Wistar rats

Male Sprague–Dawley rats

Rats

Male Wistar rats

Time of exposure APAP (once) before MECT (16 days)

Male Wistar rats

Species

Table 3. Continued

Examine the effect of EESM on liver damage induced by APAP

Evaluate the hepatoprotective effect of PdAE and PdEE against APAP and CCl4induced liver damage

APAP (500 mg/kg b.w.) orally þ EESM (100 and 200 mg/kg b.w.) orally, or APAP (500 mg/kg b.w.) orally þ silymarin (25 mg/kg b.w.) orally APAP (1000 mg/kg b.w.) orally þ PdAE (100 and 200 mg/kg b.w.) orally, or APAP (1000 mg/kg b.w.) orally þ PdEE (100 and 200 mg/ kg b.w.) orally

Examine the effect of purslane on liver damage induced by APAP

Assess the hepatoprotective efficacy of CL in liver toxicity

APAP (1000 mg/kg b.w.)þpurslane (150 mg/kg b.w.) orally, or APAP (1000 mg/kg b.w.)þvitamin C (1000 mg/kg b.w.) orally

APAP (3000 mg/kg b.w.) orally þ CL (50, 100, and 250 mg/kg b.w.) orally

APAP (3000 mg/kg b.w.) Assess the effect of EEAFA on orally þ EEAFA (50 and 100 mg/ liver damage induced by kg b.w.), orally, or APAP (3000 mg/ APAP kg b.w.) orally þ silymarin (100 mg/ kg b.w.), orally

Aim Examine the hepatoprotective effects of MECT extract against APAP-induced hepatotoxicity

Dose APAP (640 mg/kg b.w.) orally þ MECT (250 and 500 mg/kg b.w.) orally

Result/conclusion APAP: increased SGOT, SGPT, ALP, induced liver TBARS, decreased liver GSH, serum total protein levels, and resulted in large necrosis. MECT: remarkable hepatoprotective effect against APAP-induced liver damage. APAP: increased SGPT, SGOT, MDA levels, and decreased the levels of GSH, vitamin C, vitamin E, SOD, and CAT in liver. EESM: reversed these changes mentioned above. APAP: increased SGOT, SGPT, ALP, direct bilirubin, serum cholesterol, liver MDA, decreased liver GSH levels and total protein, and resulted in hepatic pathology. PdAE or PdEE: prevented the physical, biochemical and histological changes induced by APAP, and increased liver GSH level and decreased liver MDA levels. APAP: increased serum AST, ALT, ALP, GGT, liver bilirubin, protein, liver TBARS levels, decreased liver GSH levels, and reduced the activities of SOD, CAT, GPx, and GST. EEAFA: reversed these changes mentioned above. APAP: increased LDH, serum and hepatic TBARS and serum TNF-a level, decreased serum and hepatic protein thiols, and reduced GSH, SOD and GPx in blood and liver. Purslane: decreased TBARS and serum TNF-a levels, and increased serum and hepatic protein thiols as well as GSH, SOD, and GPx in blood and liver. APAP: increased serum ALP, SGOT, SGPT, lipid peroxidation, conjugated diene, and hydroperoxides in the liver tissue. CL: reversed these changes mentioned above.

Reference

(continued)

Sindhu et al. (2010)

Mohammed Abdalla and Soad Mohamed (2010)

Kuriakose and Kurup (2010)

Bhaskar and Balakrishnan 2010)

Kumar et al. (2011)

Haldar et al. (2011)

DRUG METABOLISM REVIEWS 403

APAP (once) and ERCC (7 days)

Male and female Wistar rats

APAP (2000 mg/kg b.w.) or CCl4 (0.7 mL/kg b.w.)þERCC (100, 200, and 400 mg/kg b.w.) orally

APAP (1000 mg/kg b.w.) IpþD-carnitine (500 mg/kg b.w.) Ip, or APAP (1000 mg/kg b.w.) IpþL-carnitine (500 mg/kg b.w.) Ip

APAP (once) after D-carnitine (10 days) or L-carnitine (10 days)

Male Swiss rats

Evaluate the hepatoprotective effects of ERCC extract against APAP-induced hepatotoxicity

Examine the relationship of carnitine deficiency and hepatotoxicity

Assess the hepatoprotective effect of ELPP against APAP induced acute liver damage

APAP (2000 mg/kg b.w.) orally þ ELPP (100 and 200 mg/kg b.w.) orally, or APAP (2000 mg/kg b.w.) orally þ silymarin (100 mg/kg b.w.) orally

APAP (once), 30 min after ELPP or silymarin (on day 5) and ELPP (7 days) or silymarin (7 days)

Male and female Wistar rats

Examine the association of APAP and diclofenac

Aim Evaluate the protection of quercetin and CUR against APAP-induced toxicity

Dose APAP (650 mg/kg b.w.) orally þ CUR (50 mg/kg b.w.) orally, or APAP (650 mg/kg b.w.) orally þ quercetin (20 mg/kg b.w.) orally, or APAP (650 mg/kg b.w.) orally þ NAC (150 mg/kg b.w.) orally

APAP (15, 100, 200, and 400 mg/ kg b.w.) orally þ diclofenac (3 mg/ kg b.w.) orally

APAP (7 days) with combination of diclofenac (7 days)

Male Wistar rats

Time of exposure APAP (15 days) and CUR (15 days), or NAC (15 days), or quercetin (15 days)

Male Wistar rats

Species

Table 3. Continued Result/conclusion APAP: increased plasma LDH, ALP, AST, ALT, urea, creatinine, TBARS in plasma, liver, lung, brain, heart, testes, and kidney, decreased SOD, CAT, GPx, GST levels in plasma, liver, lung, brain, heart, testes, and kidney, decreased GSH level in liver, kidney, and lung, and resulted in swollen centrilobular hepatocytes. Quercetin or CUR with APAP: successfully mitigated the rise in TBARS and restored the activities of antioxidant enzymes compared to the group treated with both APAP and NAC. The association of APAP þ diclofenac revealed a protective effect toward the toxic effects of APPA APAP þ diclofenac: increased the concentrations of AST, ALT, ALP, GPx, GR, bilirubin, and GSH APAP: increased SGPT, SGOT, total bilirubin, ALP, liver TBARS, and decreased liver GSH levels. ELPP: reversed the changes induced by APAP, and increased the level of liver GSH and significantly decreased liver TBARS levels. APAP: increased serum AST, ALP, TNF-a, liver MDA content, MPO activity, and NO content (223%), and decreased carnitine, hepatic GSH concentration. D-Carnitine: increased hepatic NO content. L-Carnitine: no effect on NO content. Pretreatment of L-carnitine: reduced hepatic NO content (72%) compared to APAP-treated animals. APAP: induced MDA content and decreased GSH, SOD, and CAT activities. Pretreatment with ERCC: prevented the increase in MDA levels and brought them near to normal level, raised GSH, SOD, and CAT levels.

Reference

(continued)

Hegde and Joshi (2009)

Arafa (2009)

Biswas et al. (2009)

Aouacheri et al. (2009)

Yousef et al. (2010)

404 X. WANG ET AL.

APAP (once) 1 minute before rPAF-AH

APAP (once) 1 minute before rPAF-AH

APAP (once) on day 5 and CPA (7 days) or silymarin (7 days) APAP (once)

APAP (once) 1 h after BC (on day 10), and BC (10 days)

Male Wistar rats

Male Wistar rats

Male and female Wistar rats

Male Wistar rats

Wistar rats

APAP (3000 mg/kg b.w.) orally þ BC (10 mg/kg b.w.) orally

Assess the hepatoprotective effects of CPA against APAP-induced liver injury

APAP (2000 mg/kg b.w.) orally þ CPA (200 and 400 mg/kg b.w.) orally, or APAP (2000 mg/kg b.w.) orally þ silymarin (100 mg/kg b.w.) orally APAP (1000 mg/kg b.w.) Ip

Examine the effect of APAP on oxidative damage to proteins and lipids in the kidney Assess the effect of BC on liver damage induced by APAP

Examine the effects of PAF inactivator, recombinant rPAF-AH on post-APAP treatment functional outcome of the liver

Examine the effects of PAF inactivator, recombinant rPAF-AH on post-APAP treatment functional outcome of the liver

APAP (3500 mg/kg b.w.) orally þ rPAF-AH (10 mg/kg b.w.) Ip

APAP (3500 mg/kg b.w.) orally þ rPAF-AH (10 mg/kg b.w.) Ip

30 days

Male Wistar rats

The hepatoprotective effect of RSME against APAP induced liver damage

Assess the hepatoprotective role of LM in APAP-induced hepatotoxicity

APAP (2000 mg/kg b.w.) orally þ LM (100, 200, and 300 mg/kg b.w.) orally, or APAP (2000 mg/kg b.w.) orally þ silymarin (150 mg/kg b.w.) orally APAP (100 mg/kg b.w.)þRSME (80 and 120 mg/kg b.w.), orally

APAP (7 days) before LM (7 days), or silymarin (7 days)

Male rats

Aim Assess the effect of DTS on liver damage induced by APAP

Dose APAP (150 mg/kg b.w. and 1.5 g/ kg b.w.) orally þ DTS (150 mg/ kg b.w.) orally

Time of exposure

Male and Female Sprague–Dawley rats APAP (once), before DS

Species

Table 3. Continued Result/conclusion

APAP: decreased the activities of GST, GPx, GSH, and GR in liver, increased serum ALP, bilirubin, SGOT, and SGPT.

APAP: increased AST, ALT, ALP, liver MDA levels, DNA fragmentation, and decreased liver protein, ATPase, protein thiol, SOD, CAT, GPx, and GSH activities. DTS: reversed these changes mentioned above. APAP: induced serum AST, ALT, ALP, liver damage. LM: protected against APAP-induced hepatotoxicity due to its potent antioxidant activity. APAP: induced SGPT, SGOT, liver TBARS, and decreased GSH and CAT activity. RSME: reduced the levels of TBARS, and increased the level of GSH and CAT activity. APAP: induced liver apoptosis and increased AST, ALT, ALP, inflammation, hepatic thymidine kinase and mitotic activity, MDA levels, cholesterol/HDL cholesterol fraction. rPAF-AH: reversed the mentioned above, decreased liver apoptosis and MDA levels. APAP: induced acute hepatic injury, alterations of ALT, AST, ALP enzymes, and liver histopathological indexes (degree of inflammation and apoptosis). rPAF-AH: decrease in hepatic MDA, the cholesterol/HDL cholesterol fraction, AST, ALT, ALP, apoptotic index, degree of inflammation, hepatic DNA biosynthesis, and hepatic thymidine kinase activity. APAP: increased SGPT, SGOT, ALP, total bilirubin, and reduced serum HDL and liver GSH levels. CPA: restored the parameters mentioned above. APAP: decreased GSH levels (4 and 24 h), and increased lipid peroxide levels (24 h).

Reference

(continued)

Kumar et al. (2005)

Abraham 2005)

Ramachandra Setty et al. (2007)

Grypioti et al. (2007b)

Grypioti et al. (2007a)

Chaturvedi and Machacha 2007)

Balamurugan 2007)

Marotta et al. (2009)

DRUG METABOLISM REVIEWS 405

Male C57BL/6J and 5-LO–/– mice

Male mice

APAP (once) or zileuton (3 days)

APAP (once) and AGO or ANTA 1 h before APAP dosing

APAP (once) and N-acetyl-cysteine amide or NAC 1.5 h after APAP dosing, and then every 12 h for 72 h

APAP (once) and flavonoids (14 days)

Female Wistar rats

Mice Male C57BL/6 mice

APAP (3 days) 4 h after diphenyl diselenide or ebselen (once)

Time of exposure

Male Wistar rats

Species

Table 3. Continued

Study the role of 5-LO in APAP-induced hepatic toxicity

Assess the hepatoprotective effects of UTR antagonist against APAP-induced liver injury

APAP (300 mg/kg b.w.) orally þ AGO (15 and 30 mg/kg b.w.) Ip þ ANTA (30 and 60 mg/kg b.w.) Ip þ the combination of AGO (30 mg/ kg b.w.) and ANTA (60 mg/kg b.w.) Ip APAP (200 mg/kg b.w.) orally þ zileuton (100 mg/kg b.w.) orally

Establish the protective effects of N-acetyl-cysteine amide

Evaluate the hepatoprotective effects of flavonoids against cyclophosphamide, vinblastine, and APAP-induced liver injury

APAP (200 mg/kg b.w.), orally þ flavonoids (60 mg/kg b.w.), orally

APAP (500 mg/kg b.w.) IpþN-acetylcysteine amide (106 mg/kg b.w.) Ip, or APAP (500 mg/kg b.w.) Ip þ NAC (106 mg/kg b.w.) Ip

Examine whether acute treatment with APAP changes delta-ALA-D activity, and if diphenyl diselenide and ebselen are protecting agents against APAP toxicity.

Aim

APAP (1200 mg/kg b.w./day) Ip þ diphenyl diselenide (100 mM/ kg b.w.) Sc or ebselen (100 mM/ kg b.w.) Sc

Dose

Result/conclusion

Lahouel et al. (2004)

Rocha et al. (2005)

Reference

(continued)

APAP: decreased liver and mitochon- Khayyat et al. (2016) drial GSH, increased MDA, ALT, glutamate dehydrogenase level, and resulted in histopathologic hepatic lesion. N-acetylcysteine amide: better than NAC in preventing oxidative stress and protecting against APAPinduced damage. N-acetylcysteine amide: increased GSH levels and the GSH/GSSG ratio in the liver, reduced the level of ALT. NAC: not effective in combating the oxidative stress induced by APAP. Palabiyik et al. (2016) APAP: increased MDA, UTR, TNF-a, and IL-1b gene expressions in liver, serum AST, ALT, decreased liver SOD, GSH, and resulted in liver damage. ANTA: increased SOD activity and GSH levels and decreased MDA levels in liver. APAP: increased serum ALT, AST, the Pu et al. (2016) gene expressions of Gst, Mrp3, Cyp2e1, Cyp3a11, IL-6, TNF-a, liver H2O2, and TBARS. Deletion or pharmacological inhibition of 5-LO: markedly ameliorated APAP-induced hepatic injury, associated with sulfotransferase 2A1 induction, CYP3A11 suppression, and hepatic transporter MRP3 reduction.

BC: exhibited a high degree of protection by reversing the altered levels induced by APAP . APAP: decreased the activity of hepatic d-ALA-D, and caused a massive reduction in non-protein-SH and vitamin C. Ebselen: restored enzyme activity caused by APAP to control values. Diphenyl diselenide: no effect on APAP-induced toxicity. APAP: increased MDA levels, and decreased GSH levels in rat liver. Flavonoids: reversed MDA and GSH levels.

406 X. WANG ET AL.

APAP (7 days) before PV (14 days)

APAP (once) after honey twice/ day (70 days) or silymarin twice/day (70 days)

Male BALB/c mice

Male Kunming mice

Male Swiss mice

APAP (2 days) after or before WPH (4 days)

APAP (once on day 13), HeA (14 days)

APAP (once) and HPE 30 min before APAP

Male Swiss mice

Mice Male Swiss mice

APAP (7 and 30 days) HomDang extract (7 and 30 days)þNAC (7 and 30 days)

Time of exposure

Female ICR Mice

Species

Table 3. Continued Result/conclusion

Examine the hepatoprotective and antioxidative potential of HeA against APAP toxicity

Assess the protective effect of WPH against APAP-induced hepato-nephrotoxicity

APAP (300 mg/kg b.w.) orally þ WPH (4 and 8 mg/kg b.w.) Ip

Wang et al. (2015)

Mohamad et al. (2015)

Hohmann et al. (2015)

Sinthorn et al. (2016)

Reference

(continued)

APAP: induced liver LPO (45%), and Ali et al. (2014) inhibited the activity of antioxidant enzymes GR (35%), GPx (40%), GST (16%), CAT (84%), and GSH (30%) contents. HeA: decreased liver LPO levels (25%) and induced antioxidant enzyme activity (GR, 15%; GPx, 17%; GST, 20%; and CAT, 60%). APAP: decreased the activities of liver Athira et al. (2013) CAT, SOD, and GPx and increased liver TBARS levels. WPH: decreased liver TBARS levels, decreased

5-LO–/– mice: GSH levels increased, oxidative stress decreased, and PPARa receptor activated. Evaluate the antioxidant and APAP: increased GPT, GOT, and hepatoprotective activity of decreased GSH and GSH/GSSG Hom-Dang extract against ratio in liver. APAP-induced toxicity Hom-Dang extract: increased GSH production and the GSH/GSSG ratio. The hepatoprotective effects of APAP: significant increase in IL-1b, HPE extract against APAPTNF-a, and IFN-c concentrations induced hepatotoxicity and MPO activity in the liver, while HPE reduce them. APAP: reduced GSH levels and antioxidant capacity in the liver, while HPE inhibited them. Examine the effect of PV on APAP: increased serum ALT, AST, liver damage induced by ALP, triglyceride, liver p450 APAP expressions, and liver MDA and NO, and decreased liver GSH, SOD, FRAP. PV: restored hepatic GSH, SOD, MDA, NO levels, and FRAP. PV: reduced the expressions of iNOS and NF-rB, the level of NO and liver cytochrome P450 protein expression significantly. Evaluate the antioxidant and APAP: increased liver index, ALT, AST, hepatoprotective activity of MDA, serum 8-OHdG levels, honey against APAPdecreased GPx and SOD activity, induced toxicity and resulted in liver damage. Vitex honey: increased serum oxygen radical absorbance capacity and decreased Cu2þ-mediate lipoprotein oxidation, increased SOD and GPx activities and decreased MDA and 8-OHdG levels.

Aim

APAP (400 mg/kg b.w.) Ip þ HeA (250 mg/kg b.w.) orally

APAP (400 mg/kg b.w.) orally þ honey (5 and 20 g/kg b.w.) orally, or APAP (400 mg/kg b.w.) orally þ silymarin (40 mg/kg b.w.) orally

APAP (250 mg/kg b.w.) orally þ PV (0.08 and 2 mL/kg b.w.) orally

APAP (1500 mg/kg b.w.) orally þ HPE (30–300 mg/kg b.w.) Ip

APAP (60 mg/kg b.w.) orally þ HomDang extract (128, 256, and 512 mg/kg b.w.) orally, or APAP (60 mg/kg b.w.) orally þ NAC (150 mg/kg b.w.) orally

Dose

DRUG METABOLISM REVIEWS 407

APAP (once) before AG or AG nanoparticles 1 h after APAP

APAP (once) and CUR (once)

APAP (7 days) before PLCS (7 days)

APAP (once) after silymarin or Smnp (7 days)

APAP (7 days) before CT (7 days)

APAP (once) before QC (6 days) or NAC (6 days)

APAP (once) before GA

Male mice

Male Wister mice

Swiss mice

Male Wister mice

Male Swiss mice

Male crossbreed Swiss mice

Time of exposure

Male Swiss mice

Species

Table 3. Continued

Design AG-loaded nanoparticles to prevent APAPinduced liver damage Investigate whether CUR could attenuate hepatitis in mice with APAP overdose

Evaluate the hepatoprotective effects of PLCS against APAP-induced hepatotoxicity Examine the protective effect of silymarin and Smnp against APAP-induced liver toxicity

Evaluate the effect of CT on liver damage induced by APAP

Investigate the ameliorative potential of QC against APAP-induced oxidative stress and biochemical alterations

Examine the hepatoprotective and antioxidant effects of GA in APAP-induced liver damage

APAP (400 mg/kg b.w.), orally þ CUR (200 and 600 mg/kg b.w.) orally

APAP (1000 mg/kg b.w.) orally þ PLCS (200 mg/kg b.w.) orally

APAP (300 mg/kg b.w.) Ip þ silymarin (125 mg/kg b.w.) Ip, or APAP (300 mg/kg b.w.) Ip þ Smnp (125 mg/kg b.w.) Ip

APAP (1000 mg/kg b.w.), orally þ CT (200 mg/kg b.w.) orally

APAP (640 mg/kg b.w.) orally þ QC (20 mg/kg b.w.) orally or APAP (640 mg/kg b.w.), orally þ NAC (150 mg/kg b.w.), orally

APAP (900 mg/kg b.w.) Ip þ GA (100 mg/kg b.w.) Ip, or APAP (900 mg/kg b.w.)Ip þ silymarin (25 mg/kg b.w.) Ip

Aim

APAP (300 mg/kg b.w.) Ip þ AG (50 mg/kg b.w.) Ip, or AG nanoparticles (50 mg/kg b.w.) Ip

Dose

Result/conclusion serum creatinine levels, and increased the liver activities of CAT, SOD and GPx, and increased serum BUN levels. APAP: increased AST, ALT, ALP, and decreased liver GSH. AG nanoparticles: decreased AST, ALT, ALP, reduced liver MDA levels and increased hepatic GSH store. APAP: increased SGOT, SGPT, MDA, IL-12, IL-18, decreased liver GSH, and resulted in extensive hemorrhagic hepatic necrosis at all zones. CUR: decreased liver MDA levels and liver IL-12 and IL-18 concentrations, and increased liver GSH levels, and decreased liver damage. APAP: increased ALT, AST, bilirubin, and liver damage. PLCS: exhibited good antioxidant capacity and protected the liver against APAP-induced oxidative damage. APAP: increased AST, ALT, ALP, and significantly decreased liver GSH levels. Silymarin and Smnp: increased liver GSH levels. Smnp: more protective effect against APAP-induced liver toxicity than silymarin. APAP: increased liver ALT, AST, and serum bilirubin levels, and necrosis, ballooning, and degeneration in hepatic plates and loss of cellular boundaries. CT: reversed the changes caused by APAP. APAP: increased erythrocytic MDA contents, ALT, AST, ALP, bilirubin, urea, creatinine, and reduced GSH, GPx, GST, SOD, and CAT activities. QC: remarkably alleviated the overproduction of MDA and improved antioxidant enzymes in APAPtreated mice blood. APAP: increased serum ALT, AST, ALP, TNF-a, and liver lipid peroxidation and decreased the activities of SOD, CAT, GST, GSH, GPx, and GR in the liver. GA: reversed the changes caused by APAP.

(continued)

Rasool et al. (2010)

Singh et al. (2011)

Nithianantham et al. (2011)

Das et al. (2011)

Jothy et al. (2012)

Somanawat et al. (2013)

Roy et al. (2013)

Reference

408 X. WANG ET AL.

APAP (once) after phyto-chemicals (7 days)

A single combined dose of APAP and RJ, or APAP (once) after RJ (7 days)

6, 24, and 48 h

APAP (once) after a1-adrenoceptor antagonists

APAP (once) before or after asteracantha

Male and Female Swiss mice

Female Swiss mice

Male Swiss mice

Male CD-1 mice

Male ICR mice

Time of exposure APAP given 3 h before MLE (7 days)

Male and Female Wister mice

Species

Table 3. Continued Dose

Aim

Result/conclusion

Investigate the antioxidant and APAP: increased SGOT, SGPT, ALP, hepatoprotective effects of bilirubin, resulted in hemolytic MLE and the determination anemia in liver. of their total phenolic MLE: possessed antioxidant activity content with hepatoprotective effects by decreasing the activity of serum SGOT, SGPT, ALP, and bilirubin. APAP (500 mg/kg b.w.), orally þ four Evaluate the hepatoprotective APAP: increased ALT, AST, ALP, liver phytochemicals (picroliv, CUR, activity of picroliv, CUR and MDA levels and decreased the ellagic acid, and silymarin) (50 and ellagic acid in comparison activity of GSH and CAT levels in 100 mg/kg b.w.), orally to silymarin against APAP liver. induced acute liver damage Picroliv, CUR, or ellagic acid: reversed the altered parameters induced by APAP toward normal values. The efficacies of these drugs were: picroliv > silymarin > CUR > ellagic acid APAP (400 mg/kg b.w.) orally þ RJ Examine the hepatoprotective APAP: increased serum ALT, AST, (200 mg/kg b.w.) orally effects of RJ against APAPALP, liver MDA levels, decreased induced hepatotoxicity liver GPx activity, led to liver parenchyma, remark cords, and sinusoids. Long-term administration of RJ: decreased liver MDA levels, increased liver GPx activity, and decreased pathological changesinduced by APAP. APAP (300 mg/kg b.w.) Ip Establish the relationship APAP: significantly increased liver between liver antioxidant MDA and nitrite þ nitrate levels at capacity and hepatic injury 6 h after APAP administration, in the early phase of acute decreased total liver SOD, and APAP intoxication copper/zinc SOD activity at alltime intervals, increased manganese SOD activity within 6 h and then decreased manganese SOD activity progressively declined in 24 and 48 h. APAP (1 or 3.5 mmol/kg b.w.) Investigate the role of APAP: decreased GSH levels and Ip þ a1-adrenoceptor antagonists endogenous catecholamines increased HO-1 gene expression. (35.7 mM/kg b.w.) Ip and a1-adrenoceptors in Prazosin: decreased HO-1 gene the development of APAPexpression, and had no effect on induced hepatotoxicity APAP-induced depletion of hepatic GSH. APAP (300 mg/kg b.w.) oralExamine the hepatoprotective Asteracantha: reduced ALT, increased ly þ asteracantha (0.9 g/kg b.w.) effects of asteracantha the GSH concentration in the liver. orally against CCl4 and APAPPretreatment: showed better results induced liver injury than post-treatment in APAP model.

APAP (1000 mg/kg b.w.) orally þ MLE (200 mg/kg b.w.) for 7 days, orally

Reference

(continued)

Hewawasam et al. (2003)

Randle et al. (2008)

Mladenovic et al. (2009)

Kanbur et al. (2009)

Girish et al. (2009)

Sasidharan et al. (2010)

DRUG METABOLISM REVIEWS 409

Dose APAP (600 mg/kg b.w.) orallyþR. stricta (1 g/kg b.w.) orally, or APAP (600 mg/kg b.w.), orallyþB. Aegyptiaca (1 g/kg b.w.), orally, or APAP (600 mg/kg b.w.), orallyþH. tuberculatum (1 g/kg b.w.) orally, or APAP (600 mg/kg b.w.), orally þ olive oil (16.7 mL/kg), orally, or APAP (600 mg/kg b.w.), orally þ silymarin (100 mg/kg b.w.) orally APAP (600 mg/kg b.w.) orally þ adenovirus-mediated gene transfer of EC-SOD (2  109 pfu)

Result/conclusion

Reference

APAP: increased plasma ALT, AST, Ali et al. (2001) prolonged the pentobarbitoneinduced sleeping time, led to atrophic cells in liver and lethality within 24 h (83%). R. stricta, B. Aegyptiaca, H. tuberculatum, and olive oil: improved liver GSH levels and protected the livers of treated mice against APAP hepatotoxicity to different degrees. Examine the hepatoprotective The adenoviral EC-SOD gene transfer: Laukkanen effects of systemic adenosignificantly attenuated release of et al. (2001) virus-mediated EC-SOD gene liver enzymes and inhibited necrotransfer against APAPsis and apoptosis. induced liver injury

Aim Assess the hepatoprotective effects of lyophilized extracts against APAPinduced liver injury

8-OHdG: 8-hydroxy-20 -deoxyguanosine; AAb: A. auriculiformis bark extract; AAep: A. auriculiformis empty pod extract; AEAP: aqueous extract of the fruiting bodies of A. polytricha; AG: andrographolide; AGO: UT-II receptor agonist; ALE: aqueous artichoke leaf extract; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AMP: aminophylline (a nonselective PDE inhibitor); ANTA: UT-II receptor antagonist; AOPP: advanced oxidation protein product; APAP: paracetamol; AST: aspartate aminotransferase; B. aegyptiaca: Balanites aegyptiaca; BC: b-carotene; BUN: blood urea nitrogen; CAT: catalase; CL: carotenoid lutein (3,30 -dihydroxybeta,epsilon-carotene); CMZ: carotenoid meso-zeaxanthin [(3R, 30 S)-beta, beta-carotene-3, 30 -diol]; CPA: ethanolic extract of C. procera flowers; CPE: Carica papaya extract; CT: Clitoria ternatea; CUR: curcumin; CYP: cytochrome P450; DRDC/AY/8060: a new polyherbal formulation containing various components; DS: methanol extract of D. salina; DTS: Denshici-to-Chiusei; EC-SOD: extracellular superoxide dismutase; EEAFA: ethanol extract of A. flos-aquae; EESM: ethanol extract of Scutia myrtina; ELPP: ethanolic extract of Peltophorum pterocarpum leaves; ERCC: ethanolic extract of the roots of C. carandas; FG: fermented ginseng; FRAP: ferric-reducing ability plasma; FRG: fermented red ginseng; GA: gallic acid; GD: glutamate dehydrogenase; GGT: gamma glutamyl transpeptidase; GOT: glutamic oxaloacetic transaminase; GPT: glutamic pyruvic transaminase; GPx: glutathione peroxidase; GR: glutathione reductase; GSH: reduced glutathione; HAREX: H. africana root extract; HDL: cholesterol/high-density lipoprotein; HeA: Habb-e-Asgand; HPE: Hypericum perforatum extract; H. tuberculatum: Haplophylum tuberculatum; iNOs: inducible nitric oxide synthase; Ip: intraperitoneal; JNK: c-Jun N-terminal kinase; LB: Lycium barbarum extract; LDH: lactate dehydrogenase; LM: Lampito mauritii; LPO: lipid peroxidation; MDA: malondialdehyde; MEAC: methanol extract of whole plant of Amaranthus caudatus; MECCF: methanolic extract of Citrullus colocynthis fruits; MECT: methanol extract of Cyperus tegetum rhizome; MEFR: methanolic extract of Ficus religiosa L.; MLE: methanolic extracts of L. edodes; MPO: myeloperoxidase; NAC: N-acetylcysteine; NSE: ethanolic extract of Nigella sativa; NO: nitric oxide; OSI: oxidative stress index; PCs: protein carbonyls; PdAE: aqueous extracts of Pergularia daemia; PdEE: ethanol extracts of Pergularia daemia; PLCS: methanol extracts from Polyalthia longifolia and Cassia spectabilis; PV: pineapple vinegar; QC: quercetin; RAAS: renin–angiotensin–aldosterone system; RGDS: red grape dried seeds; RIRA: R. imbricata rhizome acetone; RJ: Royal Jelly; rPAF-AH: recombinant platelet-activating factor acetylhydrolase; RSME: methanol extract of Raphanus sativus root; R. stricta: Rhazya stricta; Sc: subcutaneous; SGOT: serum glutamate oxaloacetate transaminase; SGPT: serum glutamate pyruvate transaminase; SH: thiols content; SIL: sildenafil (a selective PDE-5 inhibitor); Smnp: silymarin nanoparticles; SOD: superoxide dismutase; TAC: total antioxidant capacity; TAS: total antioxidant status; TOS: total oxidant status; TBARS: thiobarbituric acid reacting substances; TPP: thiamin pyrophosphate; UTR: UT-II receptor; WPH: the whey protein hydrolysate; ZZR: ethyl acetate extract of Zingiber zerumbet rhizome.

APAP given 2 days after gene transfer

Mice

Time of exposure APAP (once) after R. stricta (5 days), or B. Aegyptiaca (5 days) or H. tuberculatum (5 days) or olive oil (5 days) or silymarin (5 days)

Female OT mice

Species

Table 3. Continued

410 X. WANG ET AL.

DRUG METABOLISM REVIEWS

411

Figure 2. Oxidative stress-mediated mode of action proposed for paracetamol (APAP). Increased generation of ROS and RNS, as well as an alteration in the antioxidant status, may induce lipid, protein and DNA oxidations leading to various toxicities and apoptosis via Keap1/Nrf2/ARE, JNK and NF-jB pathways and/or the inflammatory cytokines.

increase in in vivo models suggested that there might be various differences in controlling NO generation induced by APAP between the in vitro and in vivo models, which was worthy of further investigation.

APAP-mediated oxidative damage Oxidative stress induced by APAP could change the antioxidant defense system and result in the damage

of cellular macromolecules, such as lipids, DNA and proteins (Weidinger and Kozlov 2015). Following oxidative stress, cell death can occur via apoptotic or necrotic mechanisms. During this process, DNA damage, enhanced lipid peroxidation and protein damage may appear along with the toxicity induced by APAP (Tables 1 and 3). A schematical representation of APAP-induced damage to DNA, lipids, and proteins is shown in Figure 2.

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Damage to lipids The oxidative damage to cell membrane lipids can lead to the significant increase of lipid peroxidation, which can be measured by monitoring the changes in malondialdehyde (MDA) and thiobarbituric acid reacting substances (TBARS). As one part of TBARS, MDA is the most abundant individual aldehyde resulting from lipid peroxidation, and its level is a marker of lipid oxidation (Lonare et al. 2015; Zhou et al. 2015b; Wang et al. 2016b). APAP can significantly increase lipid peroxidation in an in vitro model. After the exposure of rat hepatocytes to APAP (100 mM) for 1 h, APAP elevated MDA quantity (Simeonova et al. 2013). Various studies identified that lipid peroxidation induced by APAP in an in vivo model is a very common phenomenon. When rabbits were treated with APAP (1 g/kg b.w.) for 9 days, serum and liver MDA was increased (Zubairi et al. 2014). While in rats, different doses of APAP increased serum MDA (Arafa 2009), or hepatic MDA levels (Grypioti et al. 2007b; Hegde and Joshi 2009; Kuriakose and Kurup 2010; Ashok Kumar et al. 2011; Ekor et al. 2013; Ferah et al. 2013) and so on. Furthermore, in a study to reveal the toxic effects of APAP-induced nephrotoxicity in rats, APAP (750 mg/kg b.w.) could result in renal MDA, indicating oxidative impairments to lipid of the kidney should be drawn enough attention (Abdul Hamid et al. 2012). From Table 3, it was suggested that in rats or mice, a high dose of APAP such as 1, 2, and 3 g/ kg b.w. for administration once or for only a few days could lead to lipid peroxidation in animal serum or liver. Similarly, lipid peroxidation in animal liver or serum could also be observed at lower doses of APAP, such as 100 and 250 mg/kg b.w., when animals were treated for a long time. These phenomena suggested that lipid peroxidation induced by APAP might be a dose or time-dependent manner. In Table 3, most studies revealed that liver or serum MDA or TBARS levels were significantly increased when rats or mice were treated with an overdose of APAP. In addition, another study to investigate the ameliorative potential of quercetin (QC) against APAP-induced oxidative stress and biochemical alterations, showed that APAP could increase erythrocytic MDA contents, suggesting that overproduction of free radicals in APAPintoxicated mice might result in the erythrocytic lipid peroxidation, and consequently increased MDA contents (Singh et al. 2011). Generally, lipid peroxidation was a universal phenomenon in the oxidative stress-related toxicity of APAP in vivo and in vitro. Furthermore, previous studies

suggested that MDA induced by APAP seems to be dose- or time-dependent. Though APAP could induce oxidative damage to lipids, no studies were carried out to investigate the effects of the metabolites of APAP on lipids, which is worthy of further investigation.

Damage to DNA The threat of oxidative damage is particularly significant for DNA (Shaukat et al. 2016). The formation of the major oxidative DNA damage product 8-hydroxydeoxyguanosine (8-OH-dG) was also used as an indicator of oxidative DNA damage (Ihsan et al. 2011). Wang et al. (2015) documented that APAP (400 mg/kg b.w.) could significantly increase serum 8-OHdG levels’ formation when male mice were exposed to APAP for 70 days, suggesting that long exposure to APAP could induce DNA damage through oxidative stress. Compared with lipid peroxidation, the damage to DNA along with oxidative stress induced by APAP overdose has been reported rarely. However, it seems that long-time treatment of APAP can lead to DNA oxidative damage, indicating that this toxic effect of APAP is worthy of further investigation.

Damage to proteins Another possible major target for oxidative damage is the protein, which can be transformed into protein carbonyls upon oxidation (PCs) (Wang et al. 2016a). As a marker of global protein oxidation, PCs are generated by multiple different ROS in blood, tissues and cells (Weber et al. 2015). Advanced oxidation protein product (AOPP) also has been used to estimate the degree of oxidant-mediated protein damage, because AOPP is generated by excess ROS (Alderman et al. 2002). Though a large number of studies on oxidative stress induced by APAP have been investigated, protein peroxidation has rarely been reported. After exposure of rats to APAP (750 mg/kg b.w./day) for 7 days, APAP increased plasma PCs and renal AOPP, along with its nephrotoxicity (Abdul Hamid et al. 2012). From the previous studies, it was revealed that protein peroxidation was also one of the remarkable oxidative stress indices induced by overdose of APAP and it can occur in both plasma and kidney, suggesting that the protein peroxidation might be an important marker to indicate oxidative damage after overdose exposure of human beings and animals to APAP. However, few studies have been carried out to investigate this phenomenon and its further mechanism.

DRUG METABOLISM REVIEWS

Alterations in antioxidant status  ROS caused by O 2 , HO and hydrogen peroxide (H2O2) usually led to the alteration of the enzymatic antioxidant defense systems in in vitro and in vivo models (Yang and Lee 2015). Catalase (CAT), superoxide dismutase (SOD), GSH, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferases (GST) are the primary antioxidant enzymes, and they serve as good redox biomarkers as they are the first-line indicators of the antioxidant state through oxidation/ reduction processes (Yang and Lee 2015). As the most abundant intracellular antioxidant, GSH is involved in the protection of cells against oxidative damage and in various detoxification mechanisms (Shi et al. 2015). GSH also acts as a substrate and co-substrate in many essential enzymatic reactions involving GPx, GR, and GST, and a decrease in the GSH level usually impairs cells’ response to oxidants (Aydin 2011). As reported, APAP could lead to significant alterations in antioxidant status in in vitro models. When rat embryonic liver cells were treated with APAP (6 and 15 mM) for 24 h, APAP significantly decreased total GSH levels (GSH and oxidized (GSSG) states of GSH) with an increase in telomerase activity, suggesting a link might exist between telomerase activity and the alteration in antioxidant status induced by APAP (Bader et al. 2011). Similarly, the GSH level was significantly reduced by APAP after exposure of primary rat hepatocytes or primary monolayer cultures of rat hepatocytes to different concentrations of APAP (7 nM, 100 mM, and 12 mM) for 24 h, 1 h, or 22 h, respectively, suggesting that in in vitro models a GSH decrease is regarded as the obvious biomarker for the liver injury induced by APAP overdose (Reen et al. 2001; Simeonova et al. 2013; Zhou et al. 2015a). Damage to the antioxidative defenses was also observed in human beings (Kozer et al. 2003; Nuttall et al. 2003; Pujos-Guillot et al. 2012) (Table 2). When older persons (74 ± 1 years) were accommodated to long-term APAP treatment (3 g/day) for 14 days by increasing dietary protein intake, APAP decreased the GSH level and antioxidative defenses, indicating the ability of detoxify APAP is aging-associated based on the cysteine/GSH deficiency syndrome observed in elderly (Pujos-Guillot et al. 2012). For men and women (21.3 ± 0.8 years), after administration of APAP (1 g, four times a day) for 14 days, serum antioxidant capacity in healthy volunteers decreased (Nuttall et al. 2003). Similarly, when febrile children (2 months to 10 years) were treated with repeated supratherapeutic doses of APAP (80–180 mg/kg b.w./day) for 3–10 days, APAP decreased blood SOD and GR activity and erythrocyte

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GSH concentrations, suggesting the risk should be considered when children use APAP for a long period (Kozer et al. 2003). Most of the in vivo studies that revealed the alteration of the antioxidant defense in liver and kidney were carried out in rats, mice and rabbits (Table 3). The administration of APAP (750 mg/kg b.w./day) for 7 days induced nephrotoxicity and oxidative impairments of the kidney in rats followed by a decrease in the plasma and renal levels of GSH and plasma SOD activity (Abdul Hamid et al. 2012). In a study to reveal the effect of APAP (1 g/kg b.w.) on oxidative damage to proteins and lipids in the rat kidney, it was documented that APAP decreased GSH levels (Kumar et al. 2005). Various studies were performed to reveal the oxidative liver damage induced in rats or mice with an overdose of APAP. The dose was from 15 to 3500 mg/kg b.w., and the experiment period was from once to 8 weeks, and even up to 70 days, suggesting that both low dose with long-term administration and high dose with short-term exposure could result in liver damage, along with significant alteration in antioxidant status (Kuriakose and Kurup 2010; Sakran et al. 2014; Wang et al. 2015). In rabbits, a significant decrease in serum and liver GSH levels was also observed after the exposure of rabbits to APAP (1 g/ kg b.w.) for 9 days (Zubairi et al. 2014). Except for the GSH level, other members of the antioxidant defense system, such as CAT, SOD, GPx, GR, GST, total antioxidant capacity (TAC) activities, the reduced/oxidized glutathione (GSH/GSSG) ratio, and cellular thiol levels (total thiol [T-SH], protein thiol [P-SH], and non-protein thiol [NP-SH]) were also observed to reveal the role of oxidative stress in the liver damage induced by APAP (Table 3). It was noted that the activities of GSH, SOD, CAT, TAC, GSH/GSSG, and cellular thiol levels were decreased after exposure to APAP, suggesting the antioxidant system was weakened. Interestingly, different results in GPx activity were observed. GPx, also a key enzyme, is a cytosolic enzyme and functions in the removal of H2O2 (Sathya and Siddhuraju 2013). It was revealed that APAP increases or decreases GPx activity in rats or mice. After exposure of rats to APAP (15, 100, 200, and 400 mg/kg b.w./day) for 7 days, APAP (100 mg/ kg b.w./day) increases plasma GPx levels significantly (Biswas et al. 2009). However, in other studies carried out in rats or mice, the blood or liver GPx activity was significantly decreased after the treatment with APAP (100–3000 mg/b.w.) from just one administration to 10 days and even 8 weeks (Lahouel et al. 2004; Balamurugan 2007; Kanbur et al. 2009; Mohammed Abdalla and Soad Mohamed 2010; Sindhu et al. 2010; Singh et al. 2011; Athira et al. 2013; Okokon et al. 2013; Kisaoglu et al. 2014; Sakran et al. 2014; Senthilkumar

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et al. 2014). Though GPx is one well reported indicator of oxidative status, the levels and activities of its cofactors such as selenium and NADPH should be considered as it is a dynamic and inter-dependent defense system. Therefore, only considering the level (not even the activity) change of GPx may result in controversial findings. However, the reason for the contradictory GPx result still remains unclear, suggesting that though many phenomena of oxidative stress induced by overdose of APAP were observed, the details of its mechanism still remains unclear, and is worthy of further investigation. A misbalance of antioxidant status can be involved in the toxicities induced by overdose of APAP in vivo and in vitro. Furthermore, studies suggest that the antioxidant system, especially GSH levels as redox biomarkers, were sensitive and may be considered as good biomarkers of the toxic effects of APAP overdose.

Stress-mediated biological response Oxidative stress plays an important role in a large number of biological responses and cell signaling pathways. Thus, significant changes in gene expression and the stimulation or inhibition of signal transduction usually results in many toxicological effects. The role of APAPmediated oxidative stress in the induction of cell damage and the respective cell signaling pathways has been widely studied in vitro (Table 1) and in vivo (Table 3).

Oxidative stress, cell signaling, and inflammatory cytokines Overdoses of APAP can cause ROS generation and result in severe centrilobular hepatotoxicity and acute liver failure associated with liver congestion, necrosis, and apoptosis (Karakus et al. 2013; El Morsy and Kamel 2015). ROS production results in oxidative stress, usually stimulating various cell signaling pathways and inflammatory cytokines involved in cell damage (Galal et al. 2012; Karcioglu et al. 2015; Valvassori et al. 2015).

Keap1/Nrf2/ARE pathway The keap1/Nrf2/ARE pathway is a major cellular defense mechanism against oxidative stress (Wang et al. 2016c). When ROS are generated, Nrf2, a basic leucine-zipper transcription factor, dissociates from keap1, translocates into the nucleus, binds to antioxidant responsive elements (AREs), and behaves as a main regulator for many antioxidative and/or cytoprotective genes (Kobayashi and Yamamoto 2005; Kensler et al. 2007;

Li and Kong 2009). As reported, APAP increased ROS generation followed by the increased gene expression of Nrf2 in Hepa 1–6 mouse hepatoma cells after the exposure of cells to APAP (50 and 100 mM) for 48 h (Perez et al. 2011).

Jun-N-terminal kinase (JNK) pathway Phosphorylated JNK activates AP-1 transcription factor, which is composed of proteins including the Jun and Fos families, which regulate the expression of jun protooncogene (Jun) (Igami et al. 2015). Previous studies documented that JNK signaling could be activated by oxidative stress (Nishikawa and Araki 2007; Igami et al. 2015). Recently, it was shown that APAP (500 mg/ kg b.w.) treatment was associated with increased expression of jun as well as its downstream gene, activating transcription factor 3 (Atf3), indicating that administration may cause an acute response to liver inflammation by activating JNK signaling (Igami et al. 2015).

NF-jB pathway NF-rB is a sequence-specific transcription factor that is known to be involved in the inflammatory responses (Cao et al. 2016; Gessi et al. 2016) and it can be induced by oxidative stress (Li et al. 2013). Activation of NF-jB upregulates the expressions of inflammatory genes such as iNOS (Zamora et al. 2000). Recently, Mohamad et al. (2015) documented that administration of APAP (250 mg/kg b.w./day) for 7 days could significantly induce the level of NO production, gene expression of NF-rB and iNOS in the mouse liver, indicating that the NF-rB pathway might play an important role in inflammatory factor expressions during liver damage induced by APAP.

Inflammatory cytokines Previous studies documented that inflammatory cytokines play a critical role in the hepatotoxicity induced by overdose of APAP. It was revealed that after exposure of rats to APAP (2 g/kg b.w.), serum or plasma TNF-a levels (Ferah et al. 2013; Karakus et al. 2013; Polat et al. 2015), liver TNF-a gene levels (Karcioglu et al. 2015), serum and liver IL-1b levels (Galal et al. 2012) and plasma IL-6 levels (Karakus et al. 2013) were increased along with the appearance of oxidative stress. Similarly, other lower dose administrations of APAP also significantly increased the levels of inflammatory cytokines in rats and mice. After the exposure of rats to APAP (1 g/kg b.w.) or of mice to APAP (0.3, 0.9, or 1.5 g/ kg b.w.), serum and hepatic TNF-a levels in both rats

DRUG METABOLISM REVIEWS

and mice (Rasool et al. 2010; Sindhu et al. 2010), IL-1b, TNF-a, and IFN-c levels in mouse liver (Hohmann et al. 2015), TNF-a, and IL-1b gene expressions in mouse liver (Palabiyik et al. 2016) were increased during liver injury induced by APAP, suggesting that inflammatory cytokines significantly increases as a result of the APAP toxicity. In conclusion, the signaling pathways, including the Nrf2/HO-1, JNK, and NF-jB pathways, have been shown to be involved in the toxicity and apoptosis induced by APAP. These pathways were suggested to be closely correlated with the oxidative stress induced by APAP, suggesting that more attention needs to be paid to other signaling pathways related to oxidative stress during toxicity resulting from APAP. Furthermore, during the liver damage induced by overdose of APAP, poisoning manifests as liver damage occurring as a result of inflammation and oxidative stress.

Prevention of APAP-mediated oxidative stress A comprehensive literature search using PubMed, Web of Science, and Google Scholar was performed, and the relevant studies related with the oxidative stress and metabolism induced by APAP in vitro and in vivo were gathered. In both title and abstract, this search used the following terms for APAP and oxidative, APAP and oxidative stress, APAP and ROS, APAP and RNS, APAP and SOD, APAP and GSH, APAP and GPx, APAP and GST, APAP and GR, APAP and G6PDH, APAP and total thiol, APAP and CAT, APAP and metabolism, APAP and metabolite, respectively. Then, the articles searched in every item were summarized, and then the duplicate articles were detected and removed. We checked the abstract of the articles one by one, and the researches on the related compounds to combat the toxicity of APAP were considered as the data in this section. Oxidative stress plays a crucial role in the development of APAP-induced liver damage and nephrotoxicity (Ekor et al. 2013; El Morsy and Kamel 2015; Naggayi et al. 2015; Chellappan et al. 2016). Various compounds were investigated to combat the toxicity induced by APAP. Most of these compounds are natural plant extracts with antioxidant effects.

In vitro and in vivo studies In in vitro models, a few studies were carried out to reveal the hepatoprotective effects of APAP (Reen et al. 2001; Simeonova et al. 2013; Zhou et al. 2015a). The Swertia species extract (SSE, 100 mg/mL) in general offered relatively good protection against liver injury by increasing GSH levels when primary monolayer cultures

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of rat hepatocytes were treated with APAP (12 mM) for 22 hours (Reen et al. 2001). After exposure of rat hepatocytes to APAP (100 mM) for 1 h, saponarin, isolated from Gypsophila trichotoma, meliorated APAP-induced hepatotoxicity by restoring MDA and GSH levels in a concentration-dependent manner (Simeonova et al. 2013). In a study to reveal the protective effects of Danshen (Salvia miltiorrhiza) water extract (DSE) in primary rat hepatocytes, DSE (0.06 and 0.25 mg/mL) decreased APAP-induced total GSH depletion and preserved redox status (GSH/GSSG ratio) in hepatocytes, while DSE (0.25 and 1 mg/mL) or its active components (53.5 lM) significantly preserved GSH/GSSG ratio in hepatocytes (Zhou et al. 2015a). Various in vivo studies to investigate the protective potential of chemicals against APAP-induced toxic effects were performed rabbits (Zubairi et al. 2014), rats (Biswas et al. 2009; Abdul Hamid et al. 2012), and mice (Jothy et al. 2012; Hohmann et al. 2015). In rabbits, the hepatoprotective potential of carvedilol (10 mg/kg b.w.), prazosin (0.5 mg/kg b.w.), metoprolol (10 mg/kg b.w.), and a combination of metoprolol (10 mg/kg b.w.) and prazosin (0.5 mg/kg b.w.) in hepatotoxicity induced by APAP (1 g/kg b.w./day) for 9 days was documented. GSH was depleted after APAP treatment and returned back to the control value on prior treatment with prazosin, while carvedilol and prazosin plus metoprolol treatments significantly decreased MDA content in serum and liver homogenates (Zubairi et al. 2014). Interestingly, it was noted that different formulations and extraction reagents of antagonists showed different protective effects on the APAP-induced toxicities (Sindhu et al. 2010; Das et al. 2011). As reported, silymarin extracted from silybum marianum and silymarin nanoparticles (Smnps) were prepared by nanoprecipitation in polyvinyl alcohol stabilized Eudragit RS100V polymer. Both Sm and Smnp could increase liver GSH levels against hepatic damage when tested in an APAP overdose hepatotoxicity model, while Smnp showed a more protective effect against APAP-induced liver toxicity than Sm, suggesting that nanoparticle synchronous delivery is therefore important and exerts more hepatoprotection activity in the case of APAP overdose (Das et al. 2011). In addition, in a study to investigate the potential hepatoprotective effect against APAP, the effect was more pronounced in ethanolic extracts of air-dried leaves of purslane compared to the aqueous extract (Sindhu et al. 2010). However, the reason remains unclear, which is worthy of further investigation to interpret the difference between different extraction reagents and therefore improve the hepatoprotective effects. R

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Most research into the protective effects of chemicals were carried out in rats and mice as the liver and kidney damage models. To our knowledge, few studies have been about the protective effects against nephrotoxicity (Abdul Hamid et al. 2012). After exposure of rats to APAP (750 mg/kg b.w.) and the effects of ethyl acetate extract of Zingiber zerumbet rhizome (ZZR, 200 and 400 mg/kg b.w./day) for 7 consecutive days, ZZR reduced the intensity of renal cellular damage, renal MDA, plasma protein carbonyl, renal AOPP, and increased plasma and renal levels of GSH and plasma SOD activity, suggesting that ZZR prevented APAPinduced nephrotoxicity and oxidative impairment of the kidney (Abdul Hamid et al. 2012). In a study to investigate the antioxidant effect of whey protein hydrolysate (WPH) against hepato-nephrotoxicity induced by APAP (300 mg/kg b.w. for 2 days), WPH (4 and 8 mg/kg b.w. for 4 days) decreased the liver TBARS levels, and increased the liver activities of CAT, SOD, and GPx along with a significant increase in blood urea nitrogen (BUN) levels and decreased serum creatinine levels, suggesting that WPH mitigated the APAP-induced toxicity in both the preventive (4 mg/kg b.w. of WPH for 4 days before APAP administration) and curative (4 mg/kg b.w. of WPH for 4 days after APAP administration) groups (Athira et al. 2013). A few signaling pathways have been investigated in the protection against APAP-induced hepatotoxicity (Randle et al. 2008; Mohamad et al. 2015). The expressions of iNOS and NF-rB were significantly increased after the exposure of mice to APAP (250 mg/kg b.w./ day) for 7 days, whereas pineapple vinegar (PV, 0.08 and 2 mL/kg b.w.) treatment for 14 days reduced them (Mohamad et al. 2015). As is known, prazosin is a selective a1-adrenoceptor antagonist clinically used to treat hypertension. The peripheral vasodilatory properties of prazosin are due to a postsynaptic blockade (Randle et al. 2008). In a study to investigate the role of prazosin in the development of APAP-induced hepatotoxicity, it was revealed that prazosin (35.7 mM/kg b.w.) had no effect on APAPinduced depletion of hepatic GSH and APAP-induced transcription of the defense signaling pathway, whereas prazosin could completely prevent the hepatic erythrocyte accumulation after mice received APAP (3.5 mM/ kg b.w.) alone for 5 h (Randle et al. 2008). However, a recent study documented that prazosin (0.5 mg/kg b.w.) remarkably increased serum GSH levels and significantly decreased serum and liver MDA levels after rabbits were treated with APAP (1 g/kg b.w.) for 9 days (Zubairi et al. 2014). The reason for the conflicting results described above remains unclear. Other in vivo models carried out in rats and mice identified the various extracts from plants using ethyl

acetate, ethanol, and water and showed remarkable hepatoprotective effects against APAP-induced liver damage (Table 3). In these animal models, the antioxidant enzyme system was evaluated in the serum, liver, or kidney, revealing that APAP-induced liver or kidney toxicity was restored. The most noteworthy aspect of the decrease in the hepatic GSH activities was observed in these tests (Table 3), because when the highly toxic APAP metabolite NAPQI formed, it readily reacted with hepatic GSH and free NAPQI can cause liver damage (Chen et al. 2003). To evaluate the protective effects of various compounds, other antioxidant enzymes, such as the activities of SOD, CAT, GPx, GR, total thiols, and MPO (myeloperoxidase) were detected after exposure to both APAP and the antagonists (Table 3), the results revealed that the antagonists could significantly restore the change in these enzymes induced by an overdose of APAP.

Lipid peroxidation Lipid peroxidation is a well-established mechanism of cellular injury and is used as an indicator of oxidative stress in cells and tissues (Grypioti et al. 2007a). The increase of MDA or TBARS levels in liver was a common phenomenon caused by APAP overdose, which was from 150 to 3500 mg/kg b.w., and then an exposure period of 8 h to 30 days. The antagonists could significantly lessen lipid peroxidation and decreased MDA or TBARS levels in the liver, suggesting that they showed remarkable hepatoprotective effect (Marotta et al. 2009; Kuriakose and Kurup 2010; Ashok Kumar et al. 2011; Ekor et al. 2013; Karcioglu et al. 2015).

NO and oxygen radicals Excess free radicals such as NO and oxygen radicals, can result in oxidative stress, and caused lipid peroxidation, protein oxidation, and DNA oxidation damage (Mohamad et al. 2015; Wang et al. 2015; Palabiyik et al. 2016). In addition, PV (0.08 and 2 mL/kg b.w.) treatment for 14 days can restore the hepatic NO levels after the exposure of mice to APAP (250 mg/kg b.w./day) for 7 days (Mohamad et al. 2015). Similarly, after one administration of APAP (1 g/kg b.w.) to rats, APAP increased liver NO production, whereas thiamin pyrophosphate (TPP, 20 mg/kg b.w.) and NAC (N-acetylcysteine, 300 mg/kg b.w.) could equally decrease liver NO generation (Kisaoglu et al. 2014). Honey usually exhibited high total phenolic content, total flavonoid content, and strong antioxidant activity in 1,1-diphenyl-2picrylhydrazyl (DPPH) radical scavenging, ferric reducing antioxidant power and ferrous ion-chelating ability

DRUG METABOLISM REVIEWS

(Wang et al. 2015). In a study to evaluate its antioxidant and hepatoprotective activity against APAP-induced liver damage, it was revealed that vitex honey pretreatment (5 and 20 g/kg b.w./day) for 70 days leads to a significant increase in mice serum oxygen radical absorbance capacity, a decrease in Cu2þ-mediated lipoprotein oxidation and 8-OHdG levels formation induced by APAP (400 mg/kg b.w./day) treatment for 70 days, indicating that hepatoprotection of vitex honey against APAP-induced liver damage might attribute to its antioxidant and/or perhaps pro-oxidative property (Wang et al. 2015).

Inflammatory cytokines Inflammatory cytokines play a critical role in liver damage while antioxidants could restore their increases induced by APAP. After the exposure of rats to APAP (2 g/kg b.w.) and infliximab (3, 5, and 7 mg/kg b.w.) or NAC (140 mg/kg b.w.), both infliximab and NAC reduced serum TNF-a or IL-6 levels along with the increase in the levels of liver GSH and SOD and the decrease in MDA levels in the liver (Ferah et al. 2013; Karakus et al. 2013). As has been reported, gallic acid (GA, 100 mg/ kg b.w.) significantly reverses high serum TNF-a levels caused by APAP (900 mg/kg b.w.) (Rasool et al. 2010). Similarly, purslane (150 mg/kg b.w.) and leptin (10 and 20 mg/kg b.w.) restored rat serum TNF-a levels induced by APAP (1 or 2 g/kg b.w.), respectively (Sindhu et al. 2010; Polat et al. 2015). Galal et al. (2012) reported that honey (5, 10, and 20 g/kg b.w.) and silymarin (100 mg/kg b.w.) given prior to the administration of APAP (2 g/kg b.w.) reduced both oxidative stress and serum and liver IL-1b levels. After exposure to APAP (300 mg/kg b.w.) and the UT-II receptor antagonist (ANTA, 30 and 60 mg/kg b.w.), ANTA restored APAPinduced liver gene expression of TNF-a and IL-1b, suggesting that UT-II receptor antagonists have hepatoprotective and anti-inflammatory effects on high-dose APAP-induced hepatotoxicity in mice (Palabiyik et al. 2016). After the administration of APAP (400 mg/kg b.w.) and curcumin (CUR, 200 and 600 mg/kg b.w.), CUR significantly decreased liver IL-12 and IL-18 concentrations (Somanawat et al. 2013). A recent study showed that Hypericum perforatum extract (HPE, 30–300 mg/kg b.w.) could reduce the high levels of IL-1b, TNF-a, and IFN-c concentrations in mice caused by APAP (1.5 g/kg b.w.) (Hohmann et al. 2015).

Protective effect Various studies tested the protective effects of compounds, and it was found that most of them could

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protect against the toxicity induced by overdose of APAP. NAC, a precursor of cysteine, is usually used as an antidote for the prevention of APAP-induced hepatotoxicity. Usually, the positive control was NAC (300 mg/ kg b.w., Ip; 100, 140, 150, 300, and 1500 mg/kg b.w., orally) or silymarin (25 mg/kg b.w., Ip; 50, 100, 125, and 200 mg/kg b.w., orally) according to the Table 3. Treatment of APAP intoxication consists of administration of NAC, preferably shortly after APAP ingestion. Patients who have taken an acute oral APAP dose of >150 mg/kg b.w. (or >75 mg/kg b.w. in high-risk patients) should be treated with NAC (Wallace et al. 2002). Intravenous treatment of NAC is preferred above oral treatment. In intravenous treatment of NAC, the start dose is 150 mg/kg b.w. for 1 h infusion, and later 75 mg/kg b.w. for 4 h infusion, and the therapy is repeated until plasma APAP undetectable (Koppen et al. 2014). While in oral treatment of NAC, the start dose is 140 mg/kg b.w., and later 70 mg/kg b.w. every 4 h until 72 h after start or until plasma APAP undetectable (Koppen et al. 2014). Another positive control usually was silymarin, a known hepatoprotective agent, which is a flavonoid obtained from the plant Silybum marianum or milk thistle (Galal et al. 2012). As reported, the most widely accepted tests used for evaluating liver function are AST, ALT, and lactic dehydrogenase (LDH) activity assays (Yabe et al. 2001). When positive control was NAC, it was noted that aqueous artichoke leaf extract (ALE) (El Morsy and €ndu €z Kamel 2015), Lycium barbarum extract (LB) (Gu et al. 2015), TPP (Kisaoglu et al. 2014), infliximab (Ferah et al. 2013), b-carotene (BC) (Kumar et al. 2005), Hom-Dang extract (Sinthorn et al. 2016), QC (Singh et al. 2011) presented a similar protective effect on the liver toxicity induced by APAP. Co-administration of CUR (50 mg/kg b.w., orally) or QC (20 mg/kg b.w., orally) with APAP (650 mg/kg b.w., orally) for 15 days resulted in marked attenuation of the liver necrotic lesions, whereas administration of NAC (150 mg/ kg b.w., orally) in combination with APAP led to satisfactory protection against APAP-induced necrotic changes (Yousef et al. 2010). However, compared to NAC (300 mg/kg b.w.), TPP (20 mg/kg b.w.) more effectively reduced the activity of AST, ALT, and LDH though no statistically significant difference existed between the oxidant and anti-oxidant parameters in the TPP and NAC groups at the doses used when APAP (1000 mg/kg b.w.) was administered orally (Kisaoglu et al. 2014). Another in vivo study also suggested that low dose of NAC amide (106 mg/kg b.w.), a novel antioxidant with higher bioavailability, was better than NAC (106 mg/kg b.w.) in preventing oxidative stress

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and protecting against APAP-induced hepatotoxicity in C57BL/6 mice (Khayyat et al. 2016). When the positive control was silymarin, it was found that many compounds presented the hepatoprotective activity such as methanol extract of D. salina (DS) (Madkour and Abdel-Daim 2013), H. africana root extract (HAREX) (Okokon et al. 2013), honey (Galal et al. 2012), ethanolic extract of C. procera flowers (CPA) (Ramachandra Setty et al. 2007), GA (Rasool et al. 2010), CUR (Girish et al. 2009), and picroliv, CUR, or ellagic acid (Girish et al. 2009). However, in a study to investigate the protective effect of silymarin (125 mg/kg b.w.) and the Smnps (125 mg/kg b.w.) against liver toxicity APAP (300 mg/kg b.w.), Smnps showed more protective effect against APAP-induced liver toxicity than silymarin (Das et al. 2011). Eugenio-Perez et al. (2016) summarized the healthpromoting properties of 13 different food-derived compounds with protective effect. These compounds included CUR, a-lipoic acid, sulforaphane, lupeol, sesamol, resveratrol, apigenin, honey, silymarin, Zingiber officinale Rosc, Hibiscus sabdariffa L. extract, Aloe barbadensis miller, ALE. Up to now, various compounds were tested to decrease the toxicity induced by APAP (Figure 3). Most of them were antioxidants extracted from various plants, which decreased the generation of ROS or RNS and reduced the oxidative stress induced by APAP. However, the detoxification effects of these compounds on APAP-induced toxicity were not the same, suggesting that their detoxification mechanisms might be different. Additionally, dose formulation and extract reagents also have potential effects on the protective effect against APAP, suggesting more details of them need further interpretation. A better understanding of the detoxification mechanism will enable the discovery of new efficient antidotes for overdose of APAP, especially from natural plants.

Metabolism of APAP Metabolic pathways It was reported that about 1–4% (Oscier and Milner 2009) of the APAP dose is excreted in urine as unchanged APAP, and the majority of the dose is excreted as APAP sulfate (Xu et al. 2008; Abdul Hamid et al. 2012) (25–36%) (Winker et al. 2008) and APAP glucuronide (Bock et al. 1993; Kumar et al. 2005) (47–62%) (Winker et al. 2008). A smaller part (8–15%) is oxidized by cytochrome P450 (CYP2E1) to 3-hydroxy-APAP and the highly hepatotoxic metabolite NAPQI (Figure 4) (Winker et al. 2008; Kulo et al. 2013; Pingili et al. 2015). The metabolite, NAPQI is in its turn conjugated by GSH

into urinary excreted nontoxic thiol metabolites (cysteine, mercapturate, methylthioparacetamol, and methanesulfinylparacetamol) (Das et al. 2010). It is now recognized that the formation of APAP-protein adducts occurred simultaneously to the conjugation of NAPQI to GSH. Additionally, the methods of quantification of APAP-protein adducts are now highly sensitive (Heard et al. 2011; McGill and Jaeschke 2013; McGill et al. 2013; Mast et al. 2015).

Metabolizing enzymes APAP is normally detoxified in humans as soluble glucuronide and sulfonate by the phase II metabolizing enzymes (Roy et al. 2013). Various enzymes have been documented to be involved in the metabolism process of APAP. APAP is metabolized by CYP enzymes (CYP2E1, 1A2, 2A6, 2D6, 3A4) to a highly reactive metabolite, NAPQI (David Josephy 2005; Gumbrevicius et al. 2012). The CYP2E1 enzyme (pertaining to the oxidative enzymes of cytochrome P-450) plays an essential role in the metabolism of APAP (Gomez-Moreno et al. 2008). When the CYP2E1 enzyme metabolizes APAP, a highly hepatotoxic compound called NAPQI is formed, which can cause hepatocellular damage (Bucaretchi et al. 2014). NAPQI can be rapidly detoxified by hepatic GSH. Under conditions of excessive NAPQI formation or reduction in GSH stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of cellular proteins, forming NAPQI-protein adducts (Gumbrevicius et al. 2012).

Other factors on the metabolism and toxicity of APAP Species As documented, species is one factor that affects the metabolism and toxicity of APAP. Yu et al. (2015) reported that APAP overdose remains the leading cause of acute liver failure in humans whereas no adverse effects were observed when cynomolgus monkeys were exposed to APAP of up to 900 mg/ kg b.w./day for 14 days. In a number of cynomolgus monkeys, only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase, and glutamate dehydrogenase with no clear dose response were observed. Additionally, the Cmax values in the monkeys were up to 3.5 times those associated with human liver toxicity, and the AUC (area under curve) approx. 1000 times those associated with liver enzyme changes in 31–44% of human subjects. The

DRUG METABOLISM REVIEWS

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Figure 3. Schematic illustration of the preventive effects of different compounds including antioxidants and free radical scavengers on paracetamol-induced oxidative stress. Various antioxidants extracted from various plants can decrease ROS or RNS production, alter the status of the oxidative stress induced by APAP, and change the activities of antioxidant system after the exposure of APAP such as GSH, GSH/GSSG ration, SOD, CAT, GPx, GR, total thiols, NP-SH, T-SH, P-SH, and MPO. The levels of inflammatory cytokines such as TNF-a, IL-6, IL-1b, IL-12 and IL-18, IFN-c were decreased by the antioxidants. In a study, prazosin increased GSH level and decreased MDA content, whereas in another study, prazosin did not have effects on GSH level and completely prevent the hepatic erythrocyte accumulation after mice were received APAP. Pineapple vinegar (PV) significantly reduced the NO level and the expressions of iNOS and NF-rB.

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Figure 4. Metabolic pathways of paracetamol (APAP), effects of APAP on the metabolizing enzymes, and the oxidative stressinduced toxicity. Cited from (Bock et al. 1993; Abraham 2005; David Josephy 2005; Gomez-Moreno et al. 2008; Winker et al. 2008; Xu et al. 2008; Oscier and Milner 2009; Das et al. 2010; Radosavljevic et al. 2010; Abdul Hamid et al. 2012; Gumbrevicius et al. 2012; Kulo et al. 2013; Roy et al. 2013; Bucaretchi et al. 2014; Kisaoglu et al. 2014; Pingili et al. 2015).

study indicated that the cynomolgus monkey is remarkably resistant to APAP-induced toxicity and a poor model for investigating APAP-related hepatotoxicity in humans.

11.7 L/h) due to higher clearances of APAP glucuronide (11.6 vs. 4.76 L/h), of oxidative metabolites (4.95 vs. 2.77 L/h) and of unchanged APAP (1.15 vs. 0.75 L/h), whereas there was no difference in clearance to APAP sulfate (Kulo et al. 2013).

Age Bucaretchi et al. (2014) reported a case of APAP-induced acute liver failure in a term neonate. After receiving oral APAP (10 mg/kg b.w. every 4 h) for three consecutive days (total dose around 180 mg b.w./kg), a 26-day-old boy was admitted with slight liver enlargement along with increased serum aminotransferase activity, intestinal bleeding, shock signs, coagulopathy, metabolic acidosis, hypoglycemia, and hyperbilirubinemia, highlighting the risk of severe hepatotoxicity in neonates after multiple doses of APAP for more than two to 3 days. This case revealed that the APAP pharmacokinetics and pharmacodynamics in neonates and infants differ substantially from those in older children and adults, indicating that age plays an important role in the metabolism and toxicity of APAP.

Women at delivery and postpartum Kulo et al. (2013) documented that a higher total clearance of APAP in women (i.v., 2 g loading dose followed by 1 g every 6 h up to 24 h) at delivery compared with postpartum women (single 2 g i.v.). It was reported that the total clearance was higher in women at delivery compared with 12th postpartum week (21.1 vs.

Liver condition Liver conditions have an important effect on the liver toxicity induced by APAP overdose. In the case of depleted hepatic GSH levels as in an APAP overdose, in alcoholics, or in the case of antiretroviral therapy, cancer chemotherapy or in conditions of drug-induced liver damage (DILD), the highly toxic metabolite of APAP, NAPQI, can irreversibly bind with a number of intracellular target proteins, inducing mitochondrial oxidative stress (Knight et al. 2001). Then, the liver damage becomes more serious.

Other chemicals Tobacco smoke contains a number of substances that are capable of inducing CYP450, and enhancing the hepatotoxicity from an APAP overdose by increasing its oxidative metabolism. A previously study revealed that in patients admitted with APAP poisoning, the rate of current daily tobacco use of 70% (424 of 602 patients) was considerably higher than the rate of 31% in the background population, suggesting that current tobacco use was an independent risk factor of severe hepatotoxicity, acute liver failure and death following

DRUG METABOLISM REVIEWS

APAP overdose (Schmidt and Dalhoff 2003). It has been proven that H2O2 and O 2 are produced during metabolic activation of APAP in the CYP 450 system (Dai and Cederbaum 1995). Studies have suggested that the antioxidants showed excellent protective effects against liver and kidney damage through interfering with the metabolic process in vivo (Athira et al. 2013). These WPHs (extracts from WPH), showing excellent protective effects on APAP-induced hepato-nephrotoxicity, might have inactivated H2O2 and O 2 , which are produced during the metabolic activation of APAP in the CYP450 system (Dai and Cederbaum 1995), and restored the antioxidant defense system in the experimental mice (Athira et al. 2013). Additionally, simvastatin is a substrate of CYP3A4 enzyme. The assumption is that simvastatin may induce CYP3A4 and result in increased hepatotoxicity of APAP (Gumbrevicius et al. 2012). Consequently, metabolism of ethanol has an influencing role inhibiting the nontoxic metabolism of APAP and the detoxification of NAPQI because ethanol and APAP are detoxified by CYP2E1 (Gomez-Moreno et al. 2008). Under normal conditions, 5% of the APAP is metabolized by CYP2E1, producing NAPQI, which is rapidly detoxified by GSH to avoid hepatic damage. However, ethanol greatly increased CYP2E1 content leading to large amounts of NAPQI production, which cannot be totally detoxified by hepatic GSH. This could provoke irreversible liver damage leading to liver failure, and therefore suggests that for odontologists it is important that in chronic alcoholic patients the consumption of alcohol should not be suspended on prescribing APAP (Gomez-Moreno et al. 2008). Yoon et al. (2016) summarized the protective role of acute alcohol ingestion against APAP hepatotoxicity and the enhancement toxicity of chronic alcohol ingestion in APAPinduced hepatotoxicity by mediating the activity of CYP 2E1. As reported, DSE was a potential CYP2E1 inhibitor, and therefore, it can combat the APAP-induced toxicity through lowering the production of the toxic metabolite NAPQI (Zhou et al. 2015a). The combined administration of APAP (1 g/kg b.w., once) and D-carnitine (500 mg/kg b.w./day, 10 days) notably decreased hepatic GSH levels and increased the production of lipid peroxidation by 79% and 395% compared to control animals, respectively, whereas prior administration of L-carnitine (500 mg/kg b.w./day, 10 days) ahead of APAP (1 g/kg b.w., once) challenge, significantly increased hepatic GSH content and decreased the production of lipid peroxidation by 159% and 70% compared to APAP-treated animals, respectively (Arafa 2009). The significant difference in the effects of D-carnitine and L-carnitine on the hepatotoxicity induced by APAP indicated that the drug

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conformations might play a critical role in the biotransformation of APAP. Choline is an essential nutrient that seems to be involved in a wide variety of metabolic reactions and functions in both humans and rodents. As reported, the single administration of APAP (1 g/kg b.w., i.p.) downregulated CYP1A2 and CYP2B1 expression in cholinedeprived (CD) rats with increased liver GSH levels, while upregulating them in standard rodent chow (normally fed, NF) rats with decreased hepatic GSH levels, suggesting that CD may modify drug effectiveness and toxicity, as well as drug–drug interactions, particularly those related to APAP (Konstandi et al. 2009). It is worthy of concerning that some compounds could enhance the APAP-induced toxicity. Anti-epileptic drugs (phenobarbital, phenytoin, and carbamazepine), anti-tuberculosis drugs (isoniazid and rifampin), OTC herbs and dietary supplements (St. John’s wort, garlic, and germander), and opioid, were suggested to stimulate the CYP system and predispose patients to APAP hepatotoxicity by causing enhanced production of NAPQI via the oxidative pathway (Yoon et al. 2016). Evaluating the toxicity of APAP and other chemicals such as tobacco smoke, ethanol, and NSAIDs on humans or animals may help predict their potential effects on other organisms in human health and the food chain, which are also exposed to these agents. Metabolic enzymes were considered to play critical roles in the combination of APAP and other chemicals (Figure 4).

Oxidative stress and the metabolism of APAP As reported, APAP metabolism triggers oxidative stress, and results in lipid peroxidation, which is responsible for liver injury (Wendel et al. 1982). Additionally, the metabolic activation of APAP leads to membrane disintegration, depletion of ATP (adenosine triphosphate), DNA fragmentation and culminates in necrosis of liver cells (Jaeschke et al. 2011, 2014). It is established that a fraction of APAP is converted via the CYP450 pathway to a highly toxic metabolite, NAPQI (Dahlin et al. 1984). Once NAPQI has formed, it readily reacts with hepatic GSH and the resultant GSH-adduct is excreted in bile with multidrug resistance protein 2 (Mrp2), which mediates the hepatobiliary transport of a wide range of organic anions, including GSH-S-conjugates (e.g. leukotriene C4 and 2,4-dinitrophenyl-SGSH), and GSSG (Chen et al. 2003). During the metabolism of APAP, toxicity occurs when GSH is depleted, resulting in the conjugation of NAPQI with hepatocellular proteins leading to centrilobular liver necrosis (Kulo et al. 2013). Similarly, a number of studies have suggested that oxidative stress

- Patients treated with: APAP overdose (not mentioned the specific dose).

- Mice treated with: APAP (15 mg/g b.w.) orally or coadministration of APAP (15 mg/g b.w.) and 50 -AMP (15 mg/g b.w. and 20 mg/g b.w., respectively) orally. - L02 cells treated with: APAP (5 mM) in the presence or absence of 50 -AMP (100 lM, 200 lM, and 400 lM). - Vnn1 knockout C57BL/6 mice treated with: APAP (400 mg/kg b.w.) Ip

- C57BL/6 mice treated with: APAP (75, 150, and 300 mg/kg b.w.) Ip with and without the inhibitor of mitochondrial permeability transition, N-methyl-4isoleucine, cyclosporin (10 mg/kg b.w.) orally 1 h before APAP, or the

Human

Mice and human liver L02cell

C57BL/6 mice

Vnn1 knockout C57BL/6 mice

Mice treated with: APAP (250 mg/kg b.w.) Ip or APAP (250 mg/kg b.w.) Ip þ TFP (10 mg/kg b.w.) Ip 1 h prior APAP - Hepatocytes incubated with: APAP (1 mM), or APAP (1 mM)þTFP (10 mM).

Dose

-

Mice and freshly isolated hepatocytes

Animal species or cell type

Aim

Evaluate the role of the mitochondrial permeability transition and JNK in mitochondrial dysfunction after APAP dosing considered nontoxic by criteria of serum ALT release and histological necrosis in vivo.

Reveal the mechanism of pretreatment with clofibrate, a PPARa agonist, protecting mice from APAP injury

Investigate whether hepatic JNK activation is a consequence of oxidative stress produced during APAP metabolism

Define the relationship between circulating APAP metabolites and acute liver injury following overdose

Reveal the hepatotoxicity induced by APAP: Examine the effect of trifluoperazine (TFP), a calmodulin antagonist that inhibits calcium induced nNOS activation, on APAP hepatotoxicity and reactive nitrogen formation in APAP treated mice.

Table 4. Paracetamol (APAP) related toxicity and metabolism in recent 5 years. Result/conclusion

Clofibrate: protection not due to alterations in APAP metabolism, dependent on PPARa expression. Clofibrate: enhanced hepatic Vnn1 gene expression. Vnn1 knockout mice: more susceptible to APAP hepatotoxicity, no differences in hepatic glutathione content, gene expression of APAP metabolizing enzymes, or hepatic capacity to bioactivate or detoxify APAP ex vivo. High APAP (300 mg/kg b.w.): caused ALT release, necrosis, irreversible mitochondrial dysfunction, and hepatocellular death. APAP (150 mg/kg b.w.): caused reversible mitochondrial dysfunction and fat droplet formation in hepatocytes without ALT release or necrosis.

APAP: increased 3-nitrotyrosine in hepatic proteins and GSNO levels that were significantly decreased in the livers of APAP plus TFP treated mice APAP hepatotoxicity occurs with altered calcium metabolism and activation of nNOS leading to increased reactive nitrogen formation, and mitochondrial dysfunction. - In isolated hepatocytes, TFP inhibited APAP induced toxicity, reactive nitrogen formation (NO, GSNO, and 3-nitrotyrosine in protein), reactive oxygen formation (superoxide), loss of mitochondrial membrane potential, decreased ATP production, decreased oxygen consumption rate, and increased NADH accumulation - TFP did not alter APAP induced GSH depletion in the hepatocytes or the formation of APAP protein adducts which indicated that reactive metabolite formation was not inhibited Five APAP metabolites (two non-CYP-mediated and three CYP-mediated) were measured alongside APAP parent drug. Mild acute liver injury was associated with a reduction in the capacity to metabolize APAP. APAP metabolites can predict liver injury and have potential utility in stratified trials and for refinement of clinical decision-making. APAP: caused a feedback increase in plasma 50 -AMP. Co-administration of APAP and 50 -AMP: significantly ameliorated APAP-induced hepatotoxicity, without influences on APAP metabolism and its analgesic function. 50 -AMP: inhibited APAP-induced activation of JNK.

Reference

(continued)

Hu et al. (2016)

Ferreira et al. (2016)

Yang et al. (2017)

Vliegenthart et al. (2017)

Banerjee et al. (2017)

422 X. WANG ET AL.

Dose

- Rat treated with: APAP (0.5 g/kg b.w.) orally

- Human liver microtissues of primary human hepatocytes treated with: APAP (1.5, 4.5, 13.7, 41.2, 123 5, 370.4, 1111.1, 3333.3, and 10,000 lM) for 3 days.

- Male mice treated with: APAP (400 mg/kg b.w.) Ipþ benzyl alcohol (270 mg/kg b.w.) coadministered Ip or 2 h after APAP. - Primary mouse hepatocytes or human hepatocytes were co-treated with 5 or 10 mM APAP and 0–46 mM benzyl alcohol, or APAP or benzyl alcohol alone.

- Patients treated with: APAP overdose (not mentioned the specific dose).

Rat

HEK-293cells

C57BL/6 mice and primary mouse and human hepatocytes.

Children (2–18 years)

Akr1a-knockout mice generated after backcrossing C57BL/6N mice and Hartley guinea-pigs

- Rat liver microsomes treated with: APAP or PYPAP (1.0 mM) with or supplemented with glutathione (2 mM) and NADPH (2 mM). - Rat hepatocytes separately treated with: APAP, AMAP, PYPAP, and PYMAP (0.2 mM) or APAP and AMAP (5, 10, and 15 mM). - Male mice treated with: saline or APAP (200 and 300 mg/kg b.w.) Ip - Male Hartley guinea-pigs treated with: APAP (one dose of 1000 mg/kg b.w.) Ip

JNK inhibitor (10 mg/kg b.w.) Ip 2 h after APAP

Male Sprague–Dawley rats: rat liver microsomes and isolated rat hepatocytes

Animal species or cell type

Table 4. Continued

Examine bile acids in comparison with APAP protein adducts, an indicator of the oxidative metabolism of APAP, and ALT, the most widely used clinical indicator of liver injury.

Assess the protective mechanisms of benzyl alcohol

Identify changes in the proteome in primary three-dimensional human liver microtissues after APAP exposure

Study the toxic mechanism of APAP under conditions of alimentary protein deprivation

Reveal the mechanism of ascorbic acid protecting mice from hepatotoxicity induced by APAP

Explore the importance of the N-acyl group in APAP metabolism and toxicity

Aim

Result/conclusion

APAP: decrease in isocitrate dehydrogenase, alphaketoglutarate dehydrogenase, and malate dehydrogenase activities Alimentary protein deprivation: potentiated APAPinduced liver damage. Phase I enzymes partly metabolize APAP into its reactive NAPQI intermediate, which is conjugated to glutathione and to cellular proteins. NAPQI modification of cysteine was identified at the highest APAP concentration on four mitochondria related proteins (GATM, PARK7, PRDX6, and VDAC2) and additionally on ANXA2 and FTCD Benzyl alcohol: - protected against APAP-induced hepatotoxicity via inhibiting cytochrome P450 activities, and reduced APAP-induced oxidant stress and mitochondrial dysfunction; - alone caused mitochondrial membrane potential loss and cell toxicity, and its protective effect could not be reproduced in primary human hepatocytes, therefore benzyl alcohol is not a clinically useful treatment option for APAP overdose. Variability in bile acids in children receiving APAP: greater than in healthy children with no recent APAP exposure. Compared to bile acids, APAP protein adducts: more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to APAP, and healthy control subjects.

Ascorbic acid: ameliorating the supply of cysteine and being available for glutathione synthesis as a whole. The liver damage by APAP treatment was suppressed by ascorbic acid. Protection by ascorbic acid involves the suppression of oxidative stress caused by an APAP treatment.

Mitochondrial protein NAQPI adducts: correlated with early JNK activation, but irreversible mitochondrial depolarization and necrosis at high dose. N- or ring-substitution on APAP: decrease metabolism and toxicity, homologating the N-acyl side chain increases metabolism about two-fold, preserves the chemical reactivity of quinoneimine metabolites, and increases toxicity by up to 80fold.

(continued)

James et al. (2015)

Du et al. (2015)

Bruderer et al. (2015)

Voloshchuk and Kopylchuk (2016)

Kurahashi et al. (2016)

Koen et al. (2016)

Reference

DRUG METABOLISM REVIEWS 423

- Male mice treated with: vehicle or APAP (400 mg/kg b.w.) Ip or APAP (400 mg/kg b.w.) Ip þ SinA (200 mg/kg b.w./day); or APAP (400 mg/kg b.w.) Ip þ SinB (200 mg/kg b.w./day); or APAP (400 mg/kg b.w.) Ip þ SinC (200 mg/kg b.w./day); or APAP (400 mg/kg b.w.) Ip þ SolA (200 mg/kg b.w./day); or APAP (400 mg/kg b.w.) Ip þ SolB (200 mg/kg b.w./day);or APAP (400 mg/kg b.w.) Ip þ SthA (200 mg/kg b.w./day). The ligans are active ingredients of schisandra fructus and were given orally 12 h before APAP treatment - Primary mouse hepatic parenchymal cells treated with: APAP (0.1–50 nM).

C57BL/6 mice

- Nox4–/– mice treated orally with: APAP (200 mg/kg p.w.) and N-acetylcysteine (500 mg/kg b.w.) or APAP (200 mg/kg p.w.)þN-acetylcysteine (500 mg/kg b.w.) þ N-acetylcysteine (10 mg/mL) added to mouse drinking water 24 h prior to APAP/N-acetyl-cysteine gavage.

- Mice pre-administrated orally with: APAP (300 mg/kg b.w.), or chlorogenic acid (10 and 40 mg/kg p.w.) for 7 consecutive days, and

Nox4–/– mice and HepG2 cells

Mice and L-02 cells

Mouse hepatic parenchymal cells

- Primary human hepatocytes exposed to: APAP (0.2, 2, or 10 mM) for 24 h.

Dose

Hepatocytes

Animal species or cell type

Table 4. Continued

Test the hypothesis that APAP induced hepatocellular death in vitro depends solely on P450s. APAP cytotoxicity and APAP-protein adducts was evaluated in the presence and absence of an inhibitor of P450s, 1-minobenzotriazole Examine the role of NADPH oxidase 4 in the acetaminophen-induced hepatic injury (glutathione, methionine, cysteine, ROS, homocysteine, ALT, AST, histology and assessment of liver injury, as well as expression of Nox4 in HepG2 cells were determined between other measures) To investigate the prevention of chlorogenic acid against APAP-induced hepatotoxicity and its engaged mechanisms

Examine the protective effects of the schisandra lignans against APAPinduced acute hepatotoxicity in mice

Examine the variability in response to APAP by evaluating interindividual differences in gene expression changes and APAP metabolite formation

Aim

Result/conclusion

Chlorogenic acid: ameliorated the APAP-induced liver injury by slightly inhibiting CYP2E1 and CYP1A2 enzymatic properties.

Mice deficient in NADPH oxidase 4: markedly increased susceptibility to APAP-induced hepatic injury which could be corrected by administration of N-acetylcysteine.

APAP hepatocellular injury in vitro: a P450-dependent mechanism at concentrations of APAP 5 mM and a P450-independent mechanism at larger concentrations.

The data suggest a potential role for bile acid profiles as sensitive determinants of liver injury in drug development. The biological processes in which the genes with high interindividual variation in expression were involved include liver regeneration, inflammatory responses, mitochondrial stress responses, hepatocarcinogenesis, cell cycle, and drug efficacy. Interindividual variation in the expression of the top 1% highest variable genes were associated with variability in expression levels of hydroxyl/ methoxy-APAP and C8H13O5N-APAP-glucuronide. Pretreatment with lignans: prevented hepatic GSH depletions caused by APAP, inhibited the enzymatic activities of CYP2E1, CYP1A2, and CYP3A11, and significantly decreased the NAPQI formation.

(continued)

Pang et al. (2015)

Murray et al. (2015)

Miyakawa et al. (2015)

Jiang et al. (2015)

Jetten et al. (2016)

Reference

424 X. WANG ET AL.

Sprague–Dawley rats

Sv/129 mice

- Male rat treated with: Controlled diet with EGCG [(–)-Epigallocatechin-3-gallate] (0.54%, w/w) for 1 week and then APAP (1 g/ kg b.w.) Ip

- Rats treated orally with: APAP (100 mg/kg b.w.) alone or with quercetin (5, 10, and 20 mg/kg b.w.) and chrysin (50, 100, and 200 mg/kg b.w.) once daily for 21 consecutive days. - Male mice treated orally with: Resveratrol (100 mg/kg b.w.); or APAP (400 mg/kg b.w.) or Resveratrol (25 mg/kg b.w.)þAPAP (400 mg/kg b.w.) or Resveratrol (50 mg/kg b.w.)þAPAP (400 mg/kg b.w.) or Resveratrol (100 mg/kg b.w.)þAPAP (400 mg/kg b.w.) - Male mice treated with: APAP (400 mg/kg b.w.) Ip, or glycyrrhetinic acid (500 mg/kg b.w.) Ip for 20 days before the injection of APAP.

Rat

C57BL/6 mice

- Male NQO1 wild-type and knockout mice treated with: APAP (300 and 600 mg/kg b.w) Ip

Reveal EGCG effects on the metabolism and toxicity of APAP in rat liver

Investigate the protection mechanism of glycyrrhetinic acid toward APAPinduced liver damage using metabolomics method

Reveal hepato-protective effect of resveratrol against APAP-induced liver injury in mice and the involved mechanisms

Evaluate the effects of quercetin and chrysin on the pharmacokinetics of APAP using rats and non-everted gut sacs in vitro.

Reveal the mechanisms of the protective effect of NQO1 on APAP-induced hepatic injury

Reveal the toxicity of APAP by 3D microreactor (3D microreactor is capable of maintaining metabolically active HepG2/ C3A spheroids for over 28 days in vitro under stable oxygen gradients)

Aim (MDA, ROS, GSH levels, liver mRNA expression of CYP2E1, CYP1A2 and CYP3A11, liver mRNA expression of peroxiredoxin and other oxidative stress genes were determined, between other measures)

Dose

APAP (300 mg/kg b.w.) given on the final day. - L-02 cells (human normal liver cell line) pre-incubated with: chlorogenic acid for 15 min, and followed by incubation with APAP (10 mM/L) for 48 h. - HepG2/C3A cells exposed to: acetaminophen (1–16 mM) for four consecutive days - HeLa cells exposed to: antimycin A (10 lM), a chemical pesticide directly binding cytochrome c (HeLa cells do not express CYP2E1 or CYP3A4 and therefore cannot produce NAPQI in response to APAP exposure)

C57BL/6 mice; NQO1 wild-type and knockout mice; primary hepatocytes of NQO1 knockout mice

HepG2/C3A cells and cervical cancer HeLa cells

Animal species or cell type

Table 4. Continued

Yang et al. (2015)

Glycyrrhetinic acid: significantly protected APAPinduced toxicity (indicated by the histology of liver, the activity of ALT and AST) and prevented the elevation of palmitoylcarnitine and oleoylcarnitine induced by APAP. EGCG feeding reduced the metabolism and toxicity of APAP. EGCG: significantly reduced hepatic activities of midazolam 1-hydroxylation (CYP3A), nitrophenol 6hydroxylase (CYP2E1), UDP-glucuronosyltransferase and sulfotransferase, and reduced APAP-glucuronate and APAP-glutathione contents in plasma and

(continued)

Yao et al. (2015)

Wang et al. (2015)

Pingili et al. (2015)

Hwang et al. (2015)

Prill et al. (2016)

Reference

Resveratrol: prevented APAP-induced hepatotoxicity by inhibition of CYP2E1, CYP3A11, and CYP1A2, and by regulation of some genes to facilitate liver regeneration following APAP-induced liver injury.

NQO1 knockout mice: high sensitivity to APAP-mediated hepatotoxicity (as indicated by a large necrotic region) as well as increased levels of nitrotyrosine adducts and ROS. NQO1: protection against energy depletion caused by APAP. Quercetin and chrysin: inhibited the intestinal Pglycoprotein and metabolism of APAP, and thereby increased the systemic exposure of APAP.

NAPQI-independent targeting of mitochondrial complex III: be responsible for APAP toxicity in extrahepatic tissues. Using 3D microreactor was possible to identify subthreshold toxicity of amiodarone and identify a new mechanism of CYP2E1-independent acetaminophen toxicity involving direct mitochondrial damage.

Result/conclusion

DRUG METABOLISM REVIEWS 425

Male rat were treated with 5% acetone (v/v) 7 days for induce CYP2E1. After acetone pretreatment, rat liver microsomes and primary rat hepatocytes were isolated. Primary rat hepatocytes were pretreated for 1 h with: - Danshen (Salvia miltiorrhiza) water extract (DSE) (0.06–1 mg/mL), - Danshensu (8.2–130.5 lm), – salvianolic acid B (Sal B) (3.3–53.5 lm), Subsequently, the hepatocytes were co-cultured in the presence of APAP (7 mM, 40 mM) - Male mice treated with: APAP (250 mg/kg b.w.) Ip followed by SAMe (1.25 mM/kg b.w.) Ip 1 h after APAP - Male mice treated orally with: Wuzhi Tablet (Schisandra sphenanthera Extract) (WZ) (175, 350, or 700 mg/kg b.w.) with an interval of 12 h for 3 consecutive days þ APAP (400 mg/kg b.w.) Ip, 15 min after the last dose of WZ

- Mice treated with: APAP (300 mg/kg b.w.) Ip at Zeitgeber time and Zeitgeber time 12.

- HeLa cells treated with: APAP (5 mM).

Primary rat hepatocytes from Sprague–Dawley rats

Wild-type and Bmal1fx/ fxCreAlb mice

HeLa cells

C57BL/6 mice

C57BL/6 mice

- Monkey (three males and three females) treated orally with: APAP (900 mg/kg b.w./day) for 14 days

Dose

Cynomolgus monkeys (Macaca fascicularis)

Animal species or cell type

Table 4. Continued

Establish NQO2 as a novel off-target for APAP, determining if NQO2, which is highly expressed in human liver and kidneys, mediates APAP induced

Examine the molecular mechanisms of the protective effect of WZ on APAPinduced hepatic injury. The present study determines whether WZ exhibited an inhibitory effect on cytochrome P450-mediated metabolic activation of APAP and whether WZ could regulate the NRF2-ARE and p53/p21 signaling pathway to prevent oxidative stress and promote liver regeneration. Determine the relative contributions of the central clock and the hepatocyte circadian clock in modulating the chronotoxicity of APAP

Reveal the protective mechanism of SAMe against APAP-induced hepatotoxicity

Investigate the protective effects of DSE and its major phenolic acid components against CYP2E1-mediated APAP-induced hepatic toxicity.

Study the pharmacokinetics and metabolism of APAP in cynomolgus monkeys

Aim

Result/conclusion

Deletion of the hepatocyte clock: dramatically reduces APAP bioactivation and toxicity in vivo and in vitro because of a reduction in NADPHcytochrome P450 oxidoreductase gene expression, protein, and activity. APAP may act in part through NQO2 in the initial phase of toxicity, where increases in ROS and cytosolic Ca2þ levels concomitant with glutathione depletion.

APAP: being associated with 4-hydroxynonenal adduction of mitochondrial proteins including sarcosine dehydrogenase and carbamoyl phosphate synthase-1 whereas SAMe reduced them. WZ: inhibition of cytochrome P450-mediated APAP bioactivation, activation of the Nrf2-antioxidant response element pathway to induce detoxification and antioxidation, and regulation of the some genes to facilitate liver regeneration after APAP-induced liver injury.

liver. Toxicokinetic analysis showed good plasma exposure. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31–44% of human subjects. Metabolite profiling of urine revealed APAP and its glucuronide and sulfate metabolites. Cynomolgus monkey is remarkably resistant to APAP-induced toxicity and a poor model for investigating APAP-related hepatotoxicity in humans. DSE: protected hepatocytes against APAP-induced injury via maintenance of mitochondrial metabolic activity, inhibited CYP2E1 activity, decreased the loss of total GSH which indirectly indicated fewer formation of NAPQI. Two major components danshensu and Sal B mainly contributed to this protection. DSE, danshensu and Sal B maintained the integrity of mitochondria to certain extents which ameliorated the redox status in APAP-treated hepatocytes

(continued)

Miettinen and Bjorklund (2014)

Johnson et al. (2014)

Fan et al. (2014)

Brown et al. (2014)

Zhou et al. (2015a)

Yu et al. (2015)

Reference

426 X. WANG ET AL.

- Male mice treated with: Glycyrrhizin (GL) (400 mg/kg b.w.) Ip, 7 days, or APAP (400 mg/kg b.w.) Ip, or APAP (400 mg/kg b.w.) Ip þ GL(400 mg/kg b.w.) Ip

- Male mice treated with: APAP (200 mg/kg b.w.) Ip

- Male mice treated orally with: WZ (700 mg/kg b.w.) 7 times with an interval of 12 h, or APAP (400 mg/kg b.w.), or WZ (700 mg/kg b.w.) þ APAP (400 mg/kg b.w.)

- Healthy adult volunteers treated orally with: liquid vs. solid formulations of APAP (15 mg/kg b.w.).

- Female mice treated with: APAP (500 mg/kg b.w.) Ip

- Healthy adults treated orally with: APAP (80 mg/kg b.w.) administered as EX (665 mg tablets, 69% slow release and 31% immediate release), or as IR (500 mg tablets).

B6C3F1 mice

C57BL6 mice

Human

C57BL/6J þ/þ mice and C57BL/6J ob/ob mice

Human

Dose

C57BL/6N mice

Animal species or cell type

Table 4. Continued Aim

Investigate the pharmacokinetics and metabolism following ingestion of liquid (containing propylene glycol) vs. solid APAP preparations to see if an excipient may be conferring a hepatoprotective effect. Develop a fast and sensitive liquid chromatography–tandem mass spectrometry method to detect APAP and its glucuronide and sulfate metabolites in small volumes of plasma, and Evaluate potential modifications in APAP glucuronidation and sulfation related to obesity and nonalcoholic fatty liver disease. Examine adduct profiles in the blood samples of healthy adults that participated in a study of single dose APAP in a cross-over design comparing extended release (ER) and immediate release (IR) formulations.

Reveal the protective effect of WZ on APAP-induced hepatic injury and targeted metabolomics

Examine the temporal relationships between known indicators of APAP toxicity and metabolism (hepatic GSH and APAP protein adducts) and recognized intermediates of fatty acid b-oxidation in mitochondria, the long-chain acylcarnitines

Investigate the role of GL in mice toward APAP-induced liver toxicity in a metabolomics study

superoxide production.

Result/conclusion

APAP protein adducts: rapidly formed following nontoxic ingestion of APAP at levels significantly lower than those associated with acute liver failure. Formation rates for adducts were faster for the IR than the ER formulation. Comparison of pharmacokinetic parameters for adducts did not reveal significant differences

Serum acylcarnitines were elevated in APAP toxicity following changes in APAP adduct levels and hepatic GSH. APAP protein adducts in liver remained elevated through the time course of the toxicity. In the later stages of toxicity, at the time of liver recovery and hepatocyte regeneration, acylcarnitines fell below base-line, possibly due to heightened energy needs associated with the hepatocyte regeneration stages of toxicity. WZ: protected against APAP-induced liver injury, and blocked the increase in serum palmitoylcarnitine and oleoylcarnitine and thus restored the APAPimpaired fatty acid b-oxidation to normal levels. This study also revealed a prolonged upregulation of the PPARa target genes Cpt1 and Acot1 by WZ mainly contributing to the maintenance of normal fatty acid metabolism The CYP2E1 metabolites were lower in the liquid formulation, while there was no difference in conjugative metabolite production. Propylene glycol: an established CYP2E1 competitive antagonist, decreased susceptibility to APAP toxicity in children. APAP glucuronidation: enhanced in obese mice, suggesting that changes in APAP metabolism could modify its toxicity in obesity and related fatty liver disease.

Glycyrrhizin: protection effect against APAP-induced liver damage through reversing fatty acid metabolism. The treatment of glycyrrhizin significantly reversed the increased levels of long-chain acylcarnitines induced by APAP administration.

NQO2 mediated superoxide production may function as a novel mechanism augmenting acetaminophen toxicity.

(continued)

James et al. (2013)

Gicquel et al. (2013)

Ganetsky et al. (2013)

Bi et al. (2013)

Bhattacharyya et al. (2013)

Yu et al. (2014)

Reference

DRUG METABOLISM REVIEWS 427

Design AG loaded nanoparticles to prevent APAP-induced hepatic necrosis - Male mice treated with: APAP (300 mg/kg b.w.) Ip; or APAP (300 mg/kg b.w.)þAndrographolide (AG) (50 mg/kg b.w.) Ip, 1 h after APAP injection Swiss albino mice

50 -AMP: adenosine 50 -monophosphate; AG: andrographolide; AIF: apoptosis-inducing factor; AMAP: 30 -regioisomer; APAP: paracetamol; DSE: Danshen (Salvia miltiorrhiza) water extract; EGCG: (–)-Epigallocatechin-3gallate; GSH: reduced glutathione; GSNO: S-nitrosoglutathione; Ip: peritoneal injection; JNK: c-jun NH2-terminal protein kinase; NAPQI: N-acetyl-p-benzoquinone-imine; nNOS: neuronal nitric oxide synthase; NQO1: NAD(P)H: quinone oxidoreductase 1; NQO2: quinone reductase 2; Nrf2: nuclear factor E2-related factor 2; PPARa: peroxisome proliferator-activated receptor alpha; PYPAP and PYMAP: N-(4-pentynoyl) analogs; ROS: reactive oxygen species; SAMe: S-adenosyl-L-methionine; SinA: Schisandrin A; SinB: Schisandrin B; SinC: Schisandrin C; SolA: Schisandrol A; SolB: Schisandrol B; SthA: Schisantherin A; TFP: trifluoperazine; Vann1: Vanin-1 gen; WZ: extract of Schisandrae sphenanthera.

Roy et al. (2013)

Kulo et al. (2013) Describe the pharmacokinetics of APAP in women at delivery and in postpartum in which the different pathways were considered. - Women at delivery and post-partum treated with: APAP (2000 mg loading dose followed by 1000 mg every 6 h up to 24 h) administered intravenously following Caesarean delivery, or APAP (2000 mg loading dose) administered intravenously 10–15 weeks post-partum Human

Animal species or cell type

Table 4. Continued

Dose

Aim

Result/conclusion

Reference

X. WANG ET AL.

between the ER and IR formulations. Total clearance: being higher in women at delivery than 12th post-partum week due to higher clearances to APAP glucuronide, to oxidative metabolites and of unchanged APAP whereas no difference in clearance to APAP sulfate. The increased total APAP clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged APAP and in oxidation clearance. Engineered nanoparticles loaded with AG provided a fast protection in APAP induced acute liver failure. The new functionalized AG nanoparticles affect efficient hepatoprotection in experimental mouse APAP overdose conditions. AG nanoparticle hepatoprotection was due to the rapid regeneration of antioxidant capacity and hepatic GSH store.

428

is the mediator of APAP-induced nephrotoxicity (Aouacheri et al. 2009; Das et al. 2010). The APAP related toxicity and metabolism in recent 5 years was presented in Table 4. In summary, the hepatotoxic metabolite of APAP is regarded as NAPQI, and CYP450 enzymes play a critical role in the metabolism process of APAP. Many factors such as species, age, women at delivery and postpartum, and various chemicals, including choline, tobacco smoke, ethanol, NSAID drugs, can mediate the metabolic process of APAP. APAP metabolism triggers oxidative stress and results in lipid peroxidation, DNA oxidative damage, protein oxidation, and alterations in antioxidant status, which are responsible for liver or kidney damage.

Summary APAP is widely used as OTC analgesic and antipyretic drugs for mild to moderate pain worldwide (Rice et al. 2012; Ferah et al. 2013; Pu et al. 2016). Its overdose leads to significant liver damage paired with kidney injury in human beings and animals. Therefore, it is necessary to investigate the toxic effects and the toxicological mechanism of overdose of APAP in order to protect human beings from injury. APAP overdose is the leading cause of drug-induced acute liver failure in Western countries. It was reported that since the mid-1970s, there has been an increase in the number of APAP overdoses. In the UK, APAP has become the substance most frequently used in deliberate self-poisoning, and in Oxford, UK, the proportion of APAP overdose increased from 14.3% in 1976 to 42% in 1990, and in 1993, 47.8% of all overdoses involved APAP or APAP-containing drugs (Hawton and Fagg 1992; Hawton et al. 1996). Similar increasing trend was also noted in other countries including Denmark, Scotland, and Australia (Ott et al. 1990; Mcloone and Crombie 1996; Gow et al. 1999). Also, APAP is widely used by approximately 43 million adults in the USA every week (Blieden et al. 2014), and about 80,000 emergency room visits and around 30,000 hospitalizations annually in the USA (Nourjah et al. 2006; Budnitz et al. 2011). However, to our limited knowledge, few studies were available for the developing countries such as China, suggesting that the APAP toxicity was not paid more attention in the developing countries. As is well known, liver injury is very common in many parts of the world (Block et al. 2003; Kensler et al. 2003). Many chemicals or viruses, such as high levels of aflatoxin B1, hepatitis B and/or C virus, can result in liver damage such as hepatocellular carcinoma (HCC) in various places in the world, including Asia and sub-Saharan

DRUG METABOLISM REVIEWS

Africa, where there are upward of 500,000 new cases each year, with more than 200,000 deaths annually in the People’s Republic of China alone (Kew 2002; Wang et al. 2002). In these patients with liver damage, it is suggested that the metabolic progress of APAP might show some difference to that in healthy people, which is worthy of further investigation. Currently, most studies in in vivo models have been carried out to reveal the hepatotoxicity of APAP in healthy animals, such as normal rats and mice. To our limited knowledge, few studies have been carried out in animals with liver damage to simulate the toxic effects of APAP overdose in patients with liver damage, such as HCC. Furthermore, the combined effects of an APAP overdose and other liver-toxic compounds, such as aflatoxin B1 and microcystin, and various viruses, including hepatitis B and/or C, are worthy of further investigation to reveal the toxic effects of APAP in these models. Oxidative stress was regarded as one toxicological mechanism for APAP, based on more than several decades of research. Various studies documented that APAP shows its toxicity by oxidative stress resulting from ROS or RNS (Tables 1 and 3). It is interesting to note that oxidative stress occurs in various species of animals, such as human beings, rats, and mice, due to APAP-related toxicology. Various compounds, including free radical scavengers, can efficiently inhibit APAPinduced damage including liver and kidney injury in animal models such as rats and mice, suggesting that the toxic effects of an overdose of APAP might closely correlate with its metabolism process and oxidative stress. However, few studies have suggested that APAP does not increase oxidative stress in humans (Rice et al. 2012; Trettin et al. 2014). In a study to investigate the effects of APAP on prostacyclin, thromboxane, NO and oxidative stress in rat hepatocytes and in 4 male subjects who received a single 3 g oral dose of APAP, it was documented that even at supra-pharmacological doses of APAP, oxidative stress did not increase, and at pharmacologically relevant concentrations, APAP did not affect NO synthesis/bioavailability by recombinant human eNOS or iNOS in rat hepatocytes (Trettin et al. 2014). It was assumed that in healthy humans the APAP-induced shift of the prostacyclin/thromboxane A2 balance is counteracted by a concomitant increase in the production of circulating NO. However, the underlying mechanisms remain elusive (Trettin et al. 2014). Another study indicated that 6 months of treatment with a therapeutic dose of APAP (30 mg/kg b.w./ day) is a potent antioxidant that has been found to diminish free radicals, and decrease tunica media thickness and the amount of oxidized protein in ischemiareperfusion studies, suggesting that chronic APAP

429

treatment may decrease the oxidative stress-induced toxic effects in the rat aorta (Rice et al. 2012). It also indicates that the dose level of APAP is a key factor in the role of APAP-induced oxidative stress or acting as an antioxidant. In a study to investigate the effect of the administration of APAP (1 g/kg b.w.) on oxidative damage to proteins and lipids in the rat kidney, APAPinduced renal damage after 4 h of administration was evidenced by the elevation in plasma creatinine levels and the presence of acute tubular necrosis on histological examination of the kidney, along with no obvious changes in oxidative stress indicators, such as protein thiol, PC content and lipid peroxide levels, thiol-dependent enzyme activities and glutamine synthase, being observed in kidney, suggesting that oxidative stress may not play a causative role, but contribute to the pathogenesis of APAP-induced renal damage (Kumar et al. 2005). The fact that APAP doses used in these two studies (Rice et al. 2012; Trettin et al. 2014) were low might explain why oxidative stress did not occur. While in a study to reveal the effects of ZZR on nephrotoxicity induced by APAP (750 mg/kg b.w./day) for 7 days, the APAP group resulted in kidney damage with a significant decrease in GSH levels in plasma and kidney, a significant increase in SOD activity in plasma, a significant increase in MDA levels in plasma and kidney, and a significant increase in plasma PC content and renal AOPP (Abdul Hamid et al. 2012). Though it is difficult to know whether oxidative stress is the causative role for the kidney injury induced by APAP, a significant difference, such as PC content and lipid peroxide levels, between the study by Abraham (2005) and Abdul Hamid et al. (2012) was noted. The administration of APAP might be one probable cause, whereas the exact reason remains unclear. Therefore, although various studies focus on the role of APAP-induced oxidative stress in its toxicity, there are still many questions and even conflicting reports of APAP's role in causing oxidative stress, indicating further investigation needs to be carried out. It is interesting to note that the selective a1-adrenoceptor antagonist, prazosin (0.5 mg/kg b.w.) remarkably increased serum GSH levels and significantly decreased serum and liver MDA levels after rabbits were treated with APAP (1 g/kg b.w.) for 9 days (Zubairi et al. 2014). However, in a previous study, prazosin (35.7 mM/kg b.w.) had no effect on APAP-induced depletion of hepatic GSH after mice received APAP (3.5 mM/kg b.w.) alone for 5 h (Randle et al. 2008). The difference between the studies suggests the mechanism behind the hepatoprotection of prazosin is not well defined. However, a marked reduction in MDA levels both in serum and in

430

X. WANG ET AL.

liver homogenates, with a highly significant increase in serum GSH induced by prazosin, may suggest the antioxidant mechanism as an important factor in the hepatoprotection mechanism against APAP-induced toxicity (Zubairi et al. 2014). To protect against APAP-induced oxidative stress, a variety of compounds have been evaluated for their antioxidative effects, such as CUR, NAC, ZZR, etc., indicating that finding a good antidote for APAP is a matter of urgency, due to the large number of examples of liver or kidney toxicity induced by APAP overdose worldwide. However, the antagonist for clinical use cannot satisfy the requirement for protection against APAPinduced toxicity. In the USA, NAC administered under hospital care for a prolonged period is currently recommended as the only remedy for APAP-induced toxic effects. NAC contributes to restoring the depleted GSH store, but is associated with several side effects and is effective only within 12 h of APAP ingestion (North et al. 2010). Therefore, there is a great demand for more safe and more efficient therapeutic drugs for the toxic effects induced by APAP overdose. Further understanding of the role of oxidative stress as well as the metabolism of APAP in APAP-induced toxicity will throw fresh light on the use of antioxidants, scavengers of ROS or RNS, and therefore help to find highly safe and effective antioxidants and efficient detoxification enzymes for therapeutics in conditions like APAP-induced organ damage.

Disclosure statement No potential conflict of interest was reported by the authors.

Funding This work was supported by Grants from 948 of the Ministry of Agriculture Project (2014-S12), International Cooperation Project (4002-122002), Project of Excellence FIM UHK, Project S2013/ABI-2728 (ALIBIRD-CM Program) from Comunidad de Madrid and Project Ref. RTA2015-00010-C03-03 from Ministerio de Economıa, Industria y Competitividad, Spain.

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