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multidrug resistance protein 2 (MRP2/ABCC2) to the renal excretion of p-aminohippurate (PAH) and identification of MRP4 (ABCC4) as a novel PAH transporter, ...
AATEX 14, Special Issue, 447-452 Proc. 6th World Congress on Alternatives & Animal Use in the Life Sciences August 21-25, 2007, Tokyo, Japan

Renal drug transporters and nephrotoxicity

Naohiko Anzai1 and Hitoshi Endou1,2 1

Kyorin University School of Medicine, 2J-Pharma Co. Ltd.

Contact information: Naohiko Anzai Department of Pharmacology and Toxicology, Kyorin University School of Medicine 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan Phone: +(81)-422-47-5511 (ext. 3452), Fax: +(81)-422-79-1321, [email protected]

Abstract Among drug-induced renal failure, direct renal tubular toxicity, typically described as toxic acute tubular necrosis, is often associated with increased cellular uptake of nephrotoxic compounds. Drug transporters in tubular cells are the first fundamental stage in the development of the nephrotoxic process. Several examples can be given of organic substances that are nephrotoxic only after being transported into the cells. Recent advances in molecular cloning have identified several families of multispecific drug transporters: organic anion and cation transporter (OAT/OCT) family, organic anion-transporting polypeptide (OATP) family, type I sodium-phosphate transporters (NPTs) and ATP-dependent organic ion transporters such as MDR1/ P-glycoprotein ABCB and the multidrug resistance-associated protein (MRP) family ABCC. In addition, peptide transporter (PEPT) family and recently identified multidrug and toxin extrusion (MATE) transporters have been shown to either transport or interact with several drugs. Nephrotoxicity appears to be proportional to the final drug concentration, though the intrinsic characteristics of the drug, particularly its "reactivity", meaning its ability to react irreversibly with the intracellular targets, are also important. Knowledge of these concepts is important for the prevention of iatrogenic kidney injury, particularly in patients with underlying disease receiving concomitant treatment with several potentially nephrotoxic agents. Keywords: drug transporters, drug-induced nephrotoxicity, cephaloridine, ochratoxin A, iodipamide

Introduction Our body is always exposed to toxic organic compounds from both intentional and unintentional sources. Many hormones, neurotransmitters, and waste products of cellular metabolism as well as a wide variety of drugs are classified as organic anions and cations. To limit both systemic exposure and the duration of their pharmacological or toxicological effects, rapid and efficient elimination of these substances is fundamental defense system to our body. For organic anions and cations, active transport across the renal proximal tubule followed by elimination via the urine is a major pathway in this detoxification process. Recently, a large number of drug transport proteins belong to several different gene families have been identified and have found to be expressed in renal proximal tubules (Anzai, 2007; Table 1). These transporters, in combination with relatively high renal blood flow, predispose the kidney to increased toxic susceptibility. Understanding of the molecular mechanism of renal drug transport is essential to achieve desired therapeutic outcomes in response to drug interactions and chemical exposures,

© 2008, Japanese Society for Alternatives to Animal Experiments

to understand the progression of some disease states, and to predict the influence of genetic variation upon these processes. We discuss the current evidence implicating the function of renal drug transporters as a determinant of the toxicity of certain endogenous and xenobiotics substances. 1. Renal drug transporters A. Organic anion transporters 1) Organic Anion Transporter (OAT) family SLC22 OAT1: OAT1 mRNA is expressed predominantly in the kidneys and weakly in the brain (Sekine, 1997). In the kidneys, OAT1 protein is localized at the basolateral membrane of proximal tubular cells. OAT1-mediated uptake of PAH is stimulated by an outwardly directed concentration gradient of dicarboxylates such as á-ketoglutarate. The substrate selectivity of OAT1 is markedly broad, and these substrates include endogenous substances, such as dicarboxylates, cyclic nucleotides and prostaglandins, and exogenous substances, such as various anionic drugs and environmental compounds (Sekine, 2000).

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Table 1. Xenobiotics (Drug) Transporters

OAT2: OAT2 was originally isolated from the rat liver as a novel liver-specific transport protein with an unknown function. OAT2 is expressed predominantly in the liver and weakly in the kidneys (Sekine, 1998). The typical substrates of OAT2 are salicylate, acetylsalicylate, prostaglandin E 2 (PGE2), dicarboxylates, PAH, zidovudine (AZT) and tetracycline (Anzai, 2006). OAT3: OAT3 was isolated from the rat brain (Kusuhara, 1999). OAT3 mRNA is expressed in the kidneys, liver, brain and eye. In the kidneys, OAT3 is localized at the basolateral membrane of the proximal tubular cells. Similar to OAT1, OAT3 recognizes a broad spectrum of substrates, which mediates the high-affinity transport of PAH, estrone sulfate (ES), ochratoxin A and various drugs, including the cationic drug cimetidine in exchange for dicarboxylates inside cells (Anzai, 2006). OAT4: OAT4 was cloned from human kidneys (Cha, 2000). OAT4 mRNA is expressed in the kidneys and is localized at the apical membrane of proximal tubular cells. When expressed in Xenopus oocytes, OAT4 mediates the Na+-independent, high-affinity transport of ES, dehydroepiandrosterone sulfate, ochratoxin A, PGE2, and PGF2α (Anzai, 2006). Oat5: Oat5 was recently identified from rat kidney (Anzai, 2005). It is expressed exclusively in the kidneys and rat Oat5 is localized at the apical side of the proximal tubules. Oat5 mediates the transport of steroid sulfates as well as ochratoxin A. 2) Organic Anion Transporting Polypeptide (OATP) family SLC21/SLC0 The first member of this family, oatp1, was identified from the rat liver by an expression cloning method as a sodium-independent bile acid transporter (Jacquemin, 1994). Thus far, 11 human isoforms and 14 rat isoforms have been identified in the OATP family (Hagenbuch, 2004). Although some OATPs are selectively involved in the hepatic uptake of bulky and relatively hydrophobic organic anions, most OATPs are expressed in many tissues, such as the blood-brain barrier, choroids plexus, lungs, heart, intestine, kidneys, placenta, and testes. The OATP family is divided into six families (OATP1–OATP6). There are considerable species differences in OATP

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family among rodents and humans. Among human OATPs, only OATP4C1 is mainly expressed in the kidneys (Mikkaichi, 2004). Oatp1a3v1 (previous name: OAT-K1) and Oatp1a3v2 (previous name: OAT-K2) are specifically expressed in the rat. Oatp1a1 (previous name: oatp1), Oatp1a5 (previous name: oatp3), Oatp1a6 (previous name: oatp5), and Oatp4c1 are expressed in rodent kidneys. The orthologs of these isoforms, except OATP4C1, are absent in humans. Because of the above-mentioned remarkable species differences in OATP, it is difficult to assign distinct physiological roles to each OATP in the kidneys. There are several important substances that are preferable substrates for OATP family, which are mainly excreted via the kidneys. Recently, OATP4C1, has been revealed to be a digoxin transporter (Mikkaichi, 2004). OATP4C1 is expressed exclusively in the basolateral membrane of proximal tubular cells and mediates the high-affinity transport of digoxin (Km: 7.8 µM) and ouabain (Km: 0.38 µM), as well as thyroid hormones such as triiodothyronine (Km: 5.9 µM). 3) Sodium/Phosphate transporter Type I (NPT1) family SLC17 Molecular studies have determined that type I phosphate transporters (SLC17), a family of proteins initially characterized as phosphate carriers, expressed at the apical membrane of renal proximal tubular cells and mediate the transport of organic anions (Reimer, 2004). Mouse and human NPT1 were shown to mediate the transport of various organic anions in a chloride-dependent manner. Moreover, because human NPT1 exhibits an affinity for PAH, corresponding to previous reports using brushborder membrane vesicles, NPT1 is also suggested to represent the classical voltage-dependent PAH transporter. However, an influence of the membrane potential on PAH transport was not demonstrated (Uchino, 2000). 4) Peptide Transporter (PEPT) family SLC15 Peptide transporters are involved in electrogenic, H + -dependent transport of small peptides as well as various peptide-like drugs, such as β -lactam antibiotics, angiotensin-converting enzyme (ACE) inhibitors, and anticancer drugs (Terada, 2004). Two peptide transporters designated as PEPT1 and PEPT2 have been cloned. PEPT1, a low-affinity/highcapacity transporter, was first cloned from the rabbit intestine, and subsequently from rat and human. Rat Pept1 was localized to the apical side of intestinal epithelial cells and in early regions (S1 segments) of apical proximal tubules. PEPT2, a high-affinity/lowcapacity transporter, appeared to have different tissue localization than PEPT1 in that PEPT2 is highly expressed in the kidney but not in the intestine. Rat

Pept2 was localized to the apical side of the proximal tubule in more distal regions (S3 segments). 5) Multidrug Resistence-associated Protein (MRP) family ABCC MRP family consists of primarily active transporter with ATP-binding cassette motifs. The prototype of this family is P-gp (ford, 1990), which extrudes various hydrophobic molecules, particularly antineoplastic compounds, such as vincristine, vinblastine, adriamycin, and daunorubicin, and it confers multidrug resistance on cancer cells (Gottesman, 2002). MRP1 and MRP2 were isolated from cancer cells with multidrug resistance that do not express P-gp. In addition to antineoplastic drugs, MRP2 transports glucronides and cysteine conjugates, and it is expressed in the canalicular membrane of hepatocytes (Russel, 2002). To date, many isoforms have been identified in the MRP family, and several of these isoforms are expressed in the apical membrane of proximal tubular cells. MRP members in proximal tubular cells supposedly function as an extrusion pump for organic anions from the apical membrane, especially large and hydrophobic organic anions. Regarding the renal physiology and pharmacology, particular attention should be paid to two isoforms, namely, MRP2 and MRP4. MRP2 has been shown to transport PAH, but its affinity for PAH is low (Km: 2 mM). In contrast, human MRP4, which is also localized in the apical membrane of proximal tubular cells, transports PAH with a much higher affinity (Km: 160 µM) compared with MRP2. Furthermore, real-time PCR and Western blot analysis showed that the renal cortical expression of MRP4 is approximately fivefold higher than that of MRP2 (Smeets, 2004). These data demonstrate that MRP4 plays a certain role in the efflux of PAH and several small hydrophilic organic anions, such as urate, cAMP, and cGMP into the tubular lumen (van Aubel, 2005). B. Organic cation transporters 1) Organic Cation Transporter (OCT) family SLC22 OCT1: OCT1 was cloned from rat kidney and characterized functionally using Xenopus oocytes in 1994 (Grundemann, 1994). Rat Oct1 (rOct1) mRNA was expressed in the liver, intestine, and kidney. rOct1 protein was localized to the basolateral membrane of the S1 and S2 segments of renal proximal tubules (Koepsell, 1998). When expressed in oocytes, rOct1 stimulated its TEA uptake and inhibited by diverse organic cations. Electrophysiological study indicated that the rOct1-mediated cation transport is electrogenic. TEA uptake was decreased by acidifying the medium pH, suggesting that rOct1mediated uptale was pH sensitive. The human OCT1

mRNA expression was observed predominantly in the liver (Koepsell, 2004). OCT1 may be responsible for interspecies differences in the disposition of organic cations. OCT2: Oct2 was isolated from a rat kidney cDNA library (Okuda, 1996). Rat Oct2 (rOct2) mRNA was expressed mainly in the kidney, but not in the liver, lung, or intestine. rOct2 was localized to the basolateral membrane of the proximal tubules. rOct2 has been shown to interact with various cationic compounds, such as N-methyl-4-phenylpyridinium (MPP + ), cimetidine, NMN, nicotine, quinine, and quinidine. When expressed in oocytes, rOct2mediated TEA uptake was suppressed by the replacement of Na+ with K+, thus indicating that the rOct2 transport was membrane-potential dependent. Human OCT2 has also been identified. Interestingly, unlike rOct2, hOCT2 was localized to the apical membrane of the distal tubule (Koepsell, 2004). OCT3: OCT3 was isolated from a rat placental cDNA library and their human and mouse homologues were identified successively (Kekuda, 1998). Rodent Oct3 and human OCT3 mRNA was expressed in various tissues including the kidney. Rat OCT3 exhibited an uptake of TEA and guanidine, which was inhibited by MPP+. Electrophysiological studies revealed that rOCT3-mediated TEA uptake evoked a potential-dependent inward current, which was markedly influenced by the extracellular pH. Rat Oct3 interacted with dopamine, the neurotoxins amphetamine and methamphetamine, as well as a variety of steroids (Koepsell, 2004). The localization and intrarenal distribution of OCT3 is unknown. OCTN1: Two other members of the OCT family, OCTN1 and OCTN2, have been cloned based on their homology to OCT. OCTN1 was identified from human fetal liver (Tamai, 1997). Human OCTN1 (hOCTN1) mRNA was expressed abundantly in the kidney, trachea, bone marrow, fetal liver and several human cancer cell lines. When expressed in HEK293 cells, hOCTN1 mediated the saturable and pH-dependent TEA uptake. TEA efflux mediated by OCTN1 was also dependent on the acidic external medium pH. OCTN1 transported several drugs and endogenous compounds, including quinidine, verapamil, and carnitine (Koepsell, 2004). OCTN2: OCTN2 was identified from a human placental trophoblast cell line by homology search and their mouse and rat homologues were isolated successively (Wu, 1998). OCTN2 mRNA was detected strongly in adult human kidney, trachea, spleen, bone marrow, skeletal muscle, heart and placenta. When expressed in HEK293 cells, hOCTN2 mediated L-carnitine uptake in a sodium-dependent manner, and it also mediated the uptake of TEA and guanidine (Koepsell, 2004).

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2) MDR1/P-glycoprotein ABCB MDR1 is a member of the ABC transporter superfamily. MDR1 actively extruded drugs with diverse structures, such as vinca alkaloids, steroids, cyclosporines, tacrolimus, anthracyclines, and miscellaneous hydrophobiccations, from the cells (Ford, 1990). Although the cellular drug efflux mediated by P-gp was first identified in cancer cells, P-gp was found to be highly expressed in a number of normal tissues such as liver, pancreas, kidney, colon, and jejunum. In the kidney, MDR1 was particularly found to be concentrated on the apical surface of epithelial cells of the proximal tubules, where it secretes various drug substrates into the lumen (Thiebaut, 1987). The finding that a cardiac glycoside digoxin is actively secreted via P-gp in renal proximal tubules is clinically important for transportermediated drug interactions. 3) MATE1 Very recently, Otsuka et al. show that MATE1, a human and mouse orthologue of the multidrug and toxin extrusion family conferring multidrug resistance on bacteria, is primarily expressed in the kidney and liver, where it is localized to the luminal membranes of the renal tubules and bile canaliculi (Ohtsuka, 2005). When expressed in HEK293 cells, MATE1 mediates H + -coupled electroneutral exchange of TEA and MPP+. Its substrate specificity is similar to those of renal and hepatic H+-coupled organic cations export. Thus, MATE1 appears to be the long searched for polyspecific organic cation exporter that directly transports toxic organic cations into urine and bile. 2. Drug-induced nephrotoxicity Medications have long been associated with the development of iatrogenic renal dysfunction and injury (Choudhury, 2006). The mechanisms of druginduced nephrotoxicity can vary largely based on the pharmacologic action, metabolism, and ultimate pathway of excretion of the drug administered. Altered renal hemodynamics, which result in prerenal azotemia, is a common form of nephrotoxicity. It is often rapidly reversible upon discontinuation of the harmful medication. Intrarenal injury, especially in the renal tubular clls, may result from treatment with some types of drugs. Nephrotoxic effects may develop in glomerular and tubular epithelial cells as a result of mechanisms that disrupt normal cellular functions of mitochondria and/or membrane integrity, induce renal injury through intratubular obstruction such as crystal disposition, and promote cellular swelling and tubular luminal occulusion so called osmotic effects. Medications can also cause chronic renal failure leading to chronic interstitial injury and papillary necrosis.

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Fig. 1. Model of cephaloridine accumulation in renal tubular cells. OAT1 functions as an entrance pathway for cephaloridine and contribute to its accumulation in the proximal tubular cells. When probenecid (inhibitors of OATs) is coadministered with cephaloridine, probenecid inhibits the tubular accumulation of cephaloridine, thus reducing its potential risk.

3. Transporter-mediated nephrotoxicity Various physiological factors determine the extent of drug-induced nephrotoxicity. Transport proteins in the kidney are one of them. Several examples can be given of organic substances that are nephrotoxic only after being transported into renal tubular cells. A. Cephaloridine (antibiotics) (Fig.1) Cephalosporin antibiotics are suggested to be not only filtered through the glomeruli but also actively secreted by the proximal tubules. Cephalosporins i n h i b i t e d PA H u p t a k e i n r a t r e n a l s l i c e s a n d renal plasma membrane vesicles (Tune, 1997). Cephaloridine, a first-generation broad-spectrum cephalosporin antibiotic, is known to induce acute renal failure in humans and animals. Its nephrotoxicity is characterized by acute proximal tubular necrosis. It is mainly dependent on the accumulation and concentration of the drugs in the renal cortex. Cephaloridine possesses both anionic and cationic moieties, inhibited PAH transport but not NMN transport in basolateral membrane vesicles (Kasher, 1983). Cephalosporin antibiotics are thus considered to be secreted by the proximal tubule via PAH transporter system. Consistent with these results, we have

Fig. 2. Ochratoxin A accumulation in proximal tubular cells. OAT1 functions as an entrance pathway for ochratoxin A and contribute to its accumulation in the proximal tubular cells. When probenecid (inhibitors of OATs) or PAH (prototypical substrate for OAT1) is coadministered with ochratoxin A, they inhibit the tubular accumulation of ochratoxin A, thus reducing its potential risk.

observed that rOat1 as well as rOat3 interacts with various cephalosporin antibiotics (Jariyawat, 1999; Jung, 2002). B. Ochratoxin A (mycotoxin) (Fig.2) Ochratoxin A (OTA) is a mycotoxin, produced by Aspergillus ohraceus and Penicillium verrucosum, that contaminates cereals and is thought to be responsible for Balkan nephropathy (Pfohl-Leszkowicz, 2002), an endemic nephropathy that exhibits characteristic chronic tubulointerstitial changes and Danish porcine nephropathy. Within the body, OTA accumulates in several tissues, especially in the kidney and liver. The excretion of OTA into urine is thought to be mainly by tubular secretion, presumably via the organic anion transport system. In OAT1-expressing oocytes and OAT1-transfected cell cultures, the addition of OTA to the culture media decreases cell viability (Tsuda, 1999). This decreased cell viability is abolished by the non-toxic substrates of OAT1, such as PAH. OAT1 mediates the transmembrane transport of OTA and plays a pivotal role in the development of OTAinduced nephrotoxicity. C. Iodipamide (radio contrast agent) (Fig.3) Osmotic load of radiocontrast agents are known to cause tubular toxicity leading to tubular ischemia. But several cholegraphic agents such as Iodipamide were reported to inhibit the cellular accumulation and renal secretion of PAH, a prototypical substrate for renal OATs. Iodipamide (Billigrafin) is a watersoluble ionic dimer type iodinated X-ray contrast media similar to Iotroxic acid (Biliscopin) and Iodoxamate (Colegrafin). These agents are clinically applied to drip-infusion cholangiography (DIC). Recently, we examined the interaction of Iodipamide with OATs using their stably expressing cells (Suparat, manuscript in preparation). Iodipamide was shown to inhibit OAT1-mediated [14C]PAH uptake (IC50: 5.7 uM) and OAT3-mediated [3H]estrone sulfate uptake (IC50: 111 uM). Incubation with Iodipamide for 24 hours demonstrated its cytotoxic effect only in its higher concentration by MTT assay. We demonstrated

that OAT1 and OAT3 are likely to be the basolateral entrance pathway for Iodipamide although the mechanisms by which contrast media exert their cytotoxic effects remain uncertain. Conclusion Drug transporters, particularly OATs, are involved in the development of organ-specific toxicity of drugs and their metabolites. Besides above examples, the nephrotoxic effect of carbapenem antibiotics and antiviral drugs, such as adefovir and cidofovir are closely associated with OATs (Cihlar, 1999). The nephrotoxicity of these compounds could be reduced by the coadministration of other substrates of OATs or inhibitors of OATs. Indeed, recently, a new application of probenecid as a nephroprotectant in therapy with the antiviral drug cidofovir was determined (Lacy, 1998). When probenecid is coadministered with cidofovir, probenecid inhibits the tubular accumulation of cidofovir, leading to the reduction of its potential risk. Thus, blockade of transport by competitors eliminates or reduces the nephrotoxic response. Renal drug transporters function as an entrance pathway for several xenobiotics and contribute to their accumulation in the proximal tubular cells. It was shown that nephrotoxic compounds such as cephaloridine and ochratoxin A are the substrates for renal drug transporters by transporter-stably expressing cell lines. Use of transporter-stably expressing cells (S2-OATs) together with nonexpressing cells (S2-mock) is helpful to check the possibility of transporter-mediated nephrotoxicity. Thus, transporter-stably expressing cell lines seem to be useful systems as an animal alternative model for the screening of potential nephrotoxic compounds. Acknowledgement This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Japan Society for the Promotion of Science, Research on Health Sciences focusing on Drug Innovation from the Japan Health Sciences Foundation, Mutual Aid Corporation for Private Schools of Japan, the Salt Science Research Foundation (No. 0721), Gout Research Foundation of Japan, the Ichiro Kanehara Foundation, the Shimabara Science Promotion Foundation, and Kyorin University School of Medicine (Kyorin Medical Research Award 2006). References

Fig. 3. Proposed model of iodipamide accumulation in renal tubular cells. OAT1 and OAT3 may function as an entrance pathway for iodipamide and may contribute to its accumulation in the proximal tubular cells.

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