Human Cytochrome P450 Enzymes 5-51 as Targets of Drugs and Natural and Environmental Compounds: Mechanisms, Induction, and Inhibition—Toxic Effects and Benefits
Slobodan Rendic and F. Peter Guengerich Zagreb, Croatia and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 27232-0146 U. S. A.
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Prof. Dr. Slobodan P. Rendic Haulikova 6 HR 10000 Zagreb, Croatia Telephone: +385917393456 E-mail:
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OR
Prof. F. Peter Guengerich Department of Biochemistry Vanderbilt University School of Medicine 638B Robinson Research Building
2200 Pierce Avenue Nashville, Tennessee 37232-0146 U. S. A. Telephone: 1 (615) 322-2261 FAX: 1 (615) 343-0704 E-Mail:
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Running title: P450s 5-51
Keywords: cytochrome P450, xenobiotics, endogenous compounds, steroids, eicosanoids, vitamin D, vitamin A, retinoids, enzyme inhibition, enzyme induction
Word count: 54,064
Funding details: This work was supported in part by the U. S. National Iinstitutes of Health under Grants R01 GM118122 and R01 GM103937. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Disclosure of Interest: The authors report no conflicts of interest with the contents of this article.
Abstract
Cytochrome P450 (P450, CYP) enzymes have long been of interest due to their roles in the metabolism of drugs, pesticides, pro-carcinogens, and other xenobiotic chemicals. They have also been of interest due to their very critical roles in the biosynthesis and metabolism of steroids, vitamins, and certain eicosanoids. This review covers the 22 (of the total of 57) human P450s in Families 5-51 and their substrate selectivity. Also included is information and references regarding inducibility, inhibition, and (in some cases) stimulation by chemicals. We update and discuss important aspects of each of these 22 P450s and questions that remain open.
Introduction
The significance of the human cytochrome P450 (P450) enzymes in drug metabolism has been reviewed in detail in previous reviews (Guengerich and Rendic 2010; Rendic and Guengerich 2010, 2012; Guengerich 2015; Rendic and Guengerich 2015). In addition to a great number of compounds used as drugs or being found in the environment, and influencing the activity and/or expression of the cytochrome P450 enzymes (Guengerich and Rendic 2010; Rendic and Guengerich 2012), the effects of diseases and environmental factors—including ionizing radiation, UV, γ-rays, X-rays—are also of interest and have been
reviewed (Semonin-Holleran 1991; Klammert et al. 2009; Guengerich and Rendic 2010; Rendic and Guengerich 2012). Such factors can have profound effects on enzyme activity and expression and therefore also on the final biological activity, efficacy, and safety of drugs and other chemicals. They can contribute to drug-drug, drug-chemical, or chemicalchemical interactions by modifying the disposition of xeno- and endobiotics and consequently their fate in the body. In some cases, analysis of the results on the effects of diseases and different environmental factors on human cytochrome P450 enzymes revealed inconsistency of the reported results, making it difficult to reach conclusions.
The scope of this article is the human P450s in Families 5-51. The topic follows two relevant reviews that one of us wrote in the past four years (Guengerich 2015, 2017) on the P450s involved in metabolism of endogenous compounds. Why are we focusing on these P450s in a journal that deals with drug metabolism? There are several reasons. One is that some of the steroids and vitamins are used as drugs. Another is that most of these P450s have important roles in physiology and are subject to induction and/or inhibition by drugs. Finally, several of these P450s are functional targets for drugs, e.g. 5A1, 11B1, 11B2, 17A1, 19A1. These enzymes synthesize important molecules but over-production may be an issue in some diseases. Families 5-51 were covered in a chapter several years ago (Guengerich 2015), but here we have focused on inhibitors and also updated the information. Most of the P450 enzymes in Families 5-51 are mainly extrahepatic, with several exceptions (7A1, 8B1, 26A1, 27A1, 39A1, 51A1). In contrast to the “drug-metabolizing”
P450s in Families 1-4, the levels of expression of these enzymes are highly regulated and do not vary among individuals as much and, in general, are not very inducible by xenobiotics. Analyses of clinical tumor samples may link causality with changes in gene expression in some cases. For instance, increases/or downregulation in mRNA and/or protein expression of P450s 5A1, 7B1, 19A1, 26A1, 26B1, 26C1, 27A1, and 27B1 have been observed and suggested as markers of the aggressive biological potential of tumors and association with poor patient survival. It has been suggested that up-regulation of these enzymes might be useful as tumor markers in the diagnosis and prognosis of different malignancies. On the other hand, enhanced or lowered expression and/or activity of P450 enzymes in some diseases could result in clinically significant drug interaction potential, resulting in unfavorable clinical outcome or increased drug/chemical toxicity. Some examples include increased expression of P450 2E1 due to alcohol in healthy subjects and decreased enzyme expression in alcoholic liver disease, increased P450 2E1 expression in livers of transplant patients, high expression of P450 3A4 enzyme in lymphoid carcinoma (proposed as a useful predictor of poor response to the standard peripheral type lung cancer chemotherapy), and high expression of P450 3A enzymes in osteosarcomas (suggested as a predictor of metastasis and poor prognosis) (Guengerich and Rendic 2010). For each of the 22 P450s we will review, the format will include a brief synopsis followed by a figure showing the main reaction and a table that includes a list of physiological substrates, function, and inhibitors and inducers. We have included references following the section on each P450 for the convenience of the reader. Collectively there is a
total of 1,057 references for the entire review (not correcting for multiple entries in different sections). We have divided the review into several sections, based on the substrates for these P450s. The four sections include eicosanoids, steroids, vitamin D and related secosteroids, and retinoids. A fifth section is for P450 20A1, for which no substrates or functions have yet been characterized. This P450 remains an “orphan,” in our sense of the word (Guengerich and Cheng 2011).
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