{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T02:56:01Z","timestamp":1777517761807,"version":"3.51.4"},"reference-count":177,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T00:00:00Z","timestamp":1624320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UID\/BIM\/0009\/2020"],"award-info":[{"award-number":["UID\/BIM\/0009\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoX"],"abstract":"<jats:p>Human Cytochrome P450 (CYP) enzymes constitute a superfamily of membrane-bound hemoproteins that are responsible for the metabolism of a wide variety of clinically, physiologically, and toxicologically important compounds. These heme-thiolate monooxygenases play a pivotal role in the detoxification of xenobiotics, participating in the metabolism of many structurally diverge compounds. This short-review is intended to provide a summary on the major roles of CYPs in Phase I xenobiotic metabolism. The manuscript is focused on eight main topics that include the most relevant aspects of past and current CYP research. Initially, (I) a general overview of the main aspects of absorption, distribution, metabolism, and excretion (ADME) of xenobiotics are presented. This is followed by (II) a background overview on major achievements in the past of the CYP research field. (III) Classification and nomenclature of CYPs is briefly reviewed, followed by (IV) a summary description on CYP\u2019s location and function in mammals. Subsequently, (V) the physiological relevance of CYP as the cornerstone of Phase I xenobiotic metabolism is highlighted, followed by (VI) reviewing both genetic determinants and (VI) nongenetic factors in CYP function and activity. The last topic of the review (VIII) is focused on the current challenges of the CYP research field.<\/jats:p>","DOI":"10.3390\/jox11030007","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T23:44:02Z","timestamp":1624405442000},"page":"94-114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":436,"title":["The Central Role of Cytochrome P450 in Xenobiotic Metabolism\u2014A Brief Review on a Fascinating Enzyme Family"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3046-1313","authenticated-orcid":false,"given":"Francisco","family":"Esteves","sequence":"first","affiliation":[{"name":"Center for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Huma Toxicology, NOVA Medical School\/Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8456-7295","authenticated-orcid":false,"given":"Jos\u00e9","family":"Rueff","sequence":"additional","affiliation":[{"name":"Center for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Huma Toxicology, NOVA Medical School\/Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1362-0076","authenticated-orcid":false,"given":"Michel","family":"Kranendonk","sequence":"additional","affiliation":[{"name":"Center for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Huma Toxicology, NOVA Medical School\/Faculty of Medical Sciences, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/B978-0-12-415813-9.00003-9","article-title":"Metabolism of Xenobiotics of Human Environments","volume":"Volume 112","author":"Ernest","year":"2012","journal-title":"Progress in Molecular Biology and Translational Science"},{"key":"ref_2","unstructured":"William, S., and Louis, W.C. (1998). Handbook of Developmental Neurotoxicology, Elsevier."},{"key":"ref_3","unstructured":"Peterson, M.E., and Talcott, P.A. (2013). Small Animal Toxicology, W.B. Saunders. [3rd ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1146\/annurev-pharmtox-010611-134748","article-title":"Xenobiotic Metabolomics: Major Impact on the Metabolome","volume":"52","author":"Johnson","year":"2012","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Manikandan, P., and Nagini, S. (2018). Cytochrome P450 Structure, Function and Clinical Significance: A Review. Curr. Drug Targets, 19.","DOI":"10.2174\/1389450118666170125144557"},{"key":"ref_6","unstructured":"Simone, B., and Rupika, D. (2017). Pharmacognosy, Elsevier."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1021\/tx500444e","article-title":"Survey of Human Oxidoreductases and Cytochrome P450 Enzymes Involved in the Metabolism of Xenobiotic and Natural Chemicals","volume":"28","author":"Rendic","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1289\/ehp.98106633","article-title":"Cytochromes P450 and Species Differences in Xenobiotic Metabolism and Activation of Carcinogen","volume":"106","author":"Lewis","year":"1998","journal-title":"Environ. Health Perspect."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cld.2016.08.001","article-title":"Drug Metabolism in the Liver","volume":"21","author":"Almazroo","year":"2017","journal-title":"Clin. Liver Dis."},{"key":"ref_10","unstructured":"Miles, H., William, M., and Kenneth, B. (2009). Pharmacology, Elsevier."},{"key":"ref_11","unstructured":"Taylor, J.B., and Triggle, D.J. (2007). Comprehensive Medicinal Chemistry II, Elsevier."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1111\/bph.13785","article-title":"Trafficking and Other Regulatory Mechanisms for Organic Anion Transporting Polypeptides and Organic Anion Transporters That Modulate Cellular Drug and Xenobiotic Influx and That Are Dysregulated in Disease","volume":"174","author":"Murray","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Paxton, J. (2012). Topics on Drug Metabolism, InTech.","DOI":"10.5772\/1180"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1021\/tx700079z","article-title":"Cytochrome P450 and Chemical Toxicology","volume":"21","author":"Guengerich","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"ref_15","first-page":"467","article-title":"Amine Oxidases and Monooxygenases in the in Vivo Metabolism of Xenobiotic Amines in Humans: Has the Involvement of Amine Oxidases Been Neglected?","volume":"21","author":"Tipton","year":"2007","journal-title":"Amine Oxidases Monooxygenases Amine Metab. Hum. Fundam. Clin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1080\/03602532.2016.1225756","article-title":"Non-Cytochrome P450-Mediated Bioactivation and Its Toxicological Relevance","volume":"48","author":"Gan","year":"2016","journal-title":"Drug Metab. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/bmb.2006.49403402066","article-title":"Cytochrome P450 Enzymes in Drug Metabolism and Chemical Toxicology: An Introduction","volume":"34","author":"Furge","year":"2006","journal-title":"Biochem. Mol. Biol. Educ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jbiotec.2006.01.026","article-title":"Cytochromes P450 as Versatile Biocatalysts","volume":"124","author":"Bernhardt","year":"2006","journal-title":"J. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lyubimov, A.V. (2012). Encyclopedia of Drug Metabolism and Interactions, John Wiley & Sons, Inc.","DOI":"10.1002\/9780470921920"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0074-7696(06)60002-8","article-title":"Molecular Mechanism of Phase I and Phase II Drug-Metabolizing Enzymes: Implications for Detoxification","volume":"Volume 260","author":"Iyanagi","year":"2007","journal-title":"International Review of Cytology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Roy, U., Barber, P., Tse-Dinh, Y.-C., Batrakova, E.V., Mondal, D., and Nair, M. (2015). Role of MRP Transporters in Regulating Antimicrobial Drug Inefficacy and Oxidative Stress-Induced Pathogenesis during HIV-1 and TB Infections. Front. Microbiol., 6.","DOI":"10.3389\/fmicb.2015.00948"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"261","DOI":"10.3109\/03602532.2014.882353","article-title":"Phase 0 and Phase III Transport in Various Organs: Combined Concept of Phases in Xenobiotic Transport and Metabolism","volume":"46","author":"Petzinger","year":"2014","journal-title":"Drug Metab. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00210-006-0042-9","article-title":"Drug Transporters in Pharmacokinetics","volume":"372","author":"Petzinger","year":"2006","journal-title":"Naunyn. Schmiedebergs Arch. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2174\/138920006774832587","article-title":"Cytochrome P450 and Anticancer Drugs","volume":"7","author":"Fujita","year":"2006","journal-title":"Curr. Drug Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 Enzymes in Drug Metabolism: Regulation of Gene Expression, Enzyme Activities, and Impact of Genetic Variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ortiz de Montellano, P.R. (2015). Cytochrome P450: Structure, Mechanism, and Biochemistry, Springer International Publishing.","DOI":"10.1007\/978-3-319-12108-6"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.ctrv.2015.10.010","article-title":"Genetic Polymorphisms and Paclitaxel- or Docetaxel-Induced Toxicities: A Systematic Review","volume":"41","author":"Frederiks","year":"2015","journal-title":"Cancer Treat. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/mp.2012.42","article-title":"Genetic Variability of Drug-Metabolizing Enzymes: The Dual Impact on Psychiatric Therapy and Regulation of Brain Function","volume":"18","author":"Stingl","year":"2013","journal-title":"Mol. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1124\/dmd.116.073254","article-title":"Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism","volume":"45","author":"Annalora","year":"2017","journal-title":"Drug Metab. Dispos."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.3109\/00498258909043167","article-title":"Evolution of the Cytochrome P450 Genes","volume":"19","author":"Nebert","year":"1989","journal-title":"Xenobiotica Fate Foreign Compd. Biol. Syst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.jinorgbio.2018.06.002","article-title":"Future Perception in P450 Research","volume":"186","author":"Omura","year":"2018","journal-title":"J. Inorg. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ortiz de Montellano, P.R. (2015). Cytochrome P450, Springer International Publishing.","DOI":"10.1007\/978-3-319-12108-6"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1124\/dmd.31.12.1461","article-title":"A Passion for P450s (Rememberances of the Early History of Research on Cytochrome P450)","volume":"31","author":"Estabrook","year":"2003","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0021-9258(19)52671-0","article-title":"The Metabolism of 4-Dimethylaminoazobenzene by Rat Liver Homogenates","volume":"176","author":"Mueller","year":"1948","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/0003-9861(58)90436-3","article-title":"Pigments of Rat Liver Microsomes","volume":"75","author":"Klingenberg","year":"1958","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/0003-9861(58)90095-X","article-title":"Studies on Pig Liver Microsomes. I. Enzymic and Pigment Composition of Different Microsomal Fractions","volume":"77","author":"Garfinkel","year":"1958","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/S0021-9258(18)60338-2","article-title":"A New Cytochrome in Liver Microsomes","volume":"237","author":"Omura","year":"1962","journal-title":"J. Biol. Chem."},{"key":"ref_38","first-page":"317","article-title":"Pharmacological Implications of Microsomal Enzyme Induction","volume":"19","author":"Conney","year":"1967","journal-title":"Pharmacol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/0006-291X(68)90555-X","article-title":"Cytochrome P-450 of Liver Microsomes\u2014One Pigment or Many","volume":"30","author":"Hildebrandt","year":"1968","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1146\/annurev.pa.12.040172.000421","article-title":"Cytochrome P-450 and Its Role in Drug Metabolism","volume":"12","author":"Gillette","year":"1972","journal-title":"Annu. Rev. Pharmacol."},{"key":"ref_41","first-page":"261","article-title":"Adaptive Responses of the Liver to Foreign Compounds, with Special Reference to Microsomal Drug-Matabolizing Enzymes","volume":"1","author":"Wada","year":"1974","journal-title":"Rev. Environ. Health"},{"key":"ref_42","first-page":"207","article-title":"Induction of the Drug-Metabolizing Enzymes","volume":"6","author":"Parke","year":"1975","journal-title":"Basic Life Sci."},{"key":"ref_43","first-page":"741","article-title":"The Light Reversible Carbon Monoxide Inhibition of the Steroid C21-Hydroxylase System of the Adrenal Cortex","volume":"338","author":"Estabrook","year":"1963","journal-title":"Biochem. Z."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/S0021-9258(18)81182-6","article-title":"The Stoichiometry of C21 Hydroxylation of Steroids by Adrenocortical Microsomes","volume":"238","author":"Cooper","year":"1963","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/S0021-9258(19)56992-7","article-title":"Role of Hemoprotein P-450 in Fatty Acid Omega-Hydroxylation in a Soluble Enzyme System from Liver Microsomes","volume":"243","author":"Lu","year":"1968","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/0006-291X(74)90164-8","article-title":"A Gel-Electrophoretically Homogeneous Preparation of Cytochrome P-450 from Liver Microsomes of Phenobarbital-Pretreated Rabbits","volume":"60","author":"Imai","year":"1974","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1016\/S0021-9258(19)41552-4","article-title":"Purified Liver Microsomal Cytochrome P-450. Separation and Characterization of Multiple Forms","volume":"250","author":"Haugen","year":"1975","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/0006-291X(67)90515-3","article-title":"Studies on the Induction of CO-Binding Pigments in Liver Microsomes by Phenobarbital and 3-Methylcholanthrene","volume":"29","author":"Alvares","year":"1967","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","first-page":"186","article-title":"Induction of Drug Metabolism. II. Qualitative Differences in the Microsomal N-Demethylating Systems Stimulated by Polycyclic Hydrocarbons and by Phenobarbital","volume":"5","author":"Sladek","year":"1969","journal-title":"Mol. Pharmacol."},{"key":"ref_50","first-page":"113","article-title":"Spectral Studies of Drug Interaction with Hepatic Microsomal Cytochrome","volume":"3","author":"Schenkman","year":"1967","journal-title":"Mol. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3543","DOI":"10.1016\/S0021-9258(18)93343-0","article-title":"A Soluble Cytochrome P-450 Functional in Methylene Hydroxylation","volume":"243","author":"Katagiri","year":"1968","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/0006-291X(78)91643-1","article-title":"Aliphatic Hydroxylation by Highly Purified Liver Microsomal Cytochrome P-450. Evidence for a Carbon Radical Intermediate","volume":"81","author":"Groves","year":"1978","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3958","DOI":"10.1073\/pnas.80.13.3958","article-title":"Gene Structure of a Phenobarbital-Inducible Cytochrome P-450 in Rat Liver","volume":"80","author":"Mizukami","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1146\/annurev.bi.56.070187.004501","article-title":"P450 Genes: Structure, Evolution, and Regulation","volume":"56","author":"Nebert","year":"1987","journal-title":"Annu. Rev. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev.med.56.082103.104724","article-title":"Pharmacogenomics and Individualized Drug Therapy","volume":"57","author":"Eichelbaum","year":"2006","journal-title":"Annu. Rev. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/toxsci\/kfq374","article-title":"Genetic Polymorphism and Toxicology\u2014With Emphasis on Cytochrome P450","volume":"120","author":"Johansson","year":"2011","journal-title":"Toxicol. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1517\/14622416.5.7.895","article-title":"Genetic Variation in Eleven Phase I Drug Metabolism Genes in an Ethnically Diverse Population","volume":"5","author":"Solus","year":"2004","journal-title":"Pharmacogenomics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"850","DOI":"10.2174\/138920021610151210164501","article-title":"Role of Metabolic Enzymes P450 (CYP) on Activating Procarcinogen and Their Polymorphisms on the Risk of Cancers","volume":"16","author":"He","year":"2015","journal-title":"Curr. Drug Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1126\/science.1136678","article-title":"Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes","volume":"315","author":"Stranger","year":"2007","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.taap.2005.01.030","article-title":"The Human Genome Project and Novel Aspects of Cytochrome P450 Research","volume":"207","year":"2005","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/1479-7364-4-1-59","article-title":"The Cytochrome P450 Homepage","volume":"4","author":"Nelson","year":"2009","journal-title":"Hum. Genomics"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5597","DOI":"10.1073\/pnas.88.13.5597","article-title":"Expression and Enzymatic Activity of Recombinant Cytochrome P450 17 Alpha-Hydroxylase in Escherichia Coli","volume":"88","author":"Barnes","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"7321","DOI":"10.1016\/S0021-9258(20)89447-2","article-title":"Alcohol-Inducible Cytochrome P-450IIE1 Lacking the Hydrophobic NH2-Terminal Segment Retains Catalytic Activity and Is Membrane-Bound When Expressed in Escherichia Coli","volume":"266","author":"Larson","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"19186","DOI":"10.1016\/S0021-9258(18)54980-2","article-title":"The Expression of a Catalytically Active Cholesterol 7 Alpha-Hydroxylase Cytochrome P450 in Escherichia Coli","volume":"266","author":"Li","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_65","first-page":"759","article-title":"High-Level Expression of Functional Human Cytochrome P450 1A2 in Escherichia Coli","volume":"6","author":"Fisher","year":"1992","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/mutage\/13.3.263","article-title":"Expression of Human Cytochrome P450 1A2 in Escherichia Coli: A System for Biotransformation and Genotoxicity Studies of Chemical Carcinogens","volume":"13","author":"Kranendonk","year":"1998","journal-title":"Mutagenesis"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S1383-5718(99)00032-7","article-title":"Escherichia Coli MTC, a Human NADPH P450 Reductase Competent Mutagenicity Tester Strain for the Expression of Human Cytochrome P450 Isoforms 1A1, 1A2, 2A6, 3A4, or 3A5: Catalytic Activities and Mutagenicity Studies","volume":"441","author":"Kranendonk","year":"1999","journal-title":"Mutat. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"16122","DOI":"10.1016\/S0021-9258(17)36209-9","article-title":"The 2.6-A Crystal Structure of Pseudomonas Putida Cytochrome P-450","volume":"260","author":"Poulos","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/0022-2836(87)90190-2","article-title":"High-Resolution Crystal Structure of Cytochrome P450cam","volume":"195","author":"Poulos","year":"1987","journal-title":"J. Mol. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1126\/science.8342039","article-title":"Crystal Structure of Hemoprotein Domain of P450BM-3, a Prototype for Microsomal P450\u2019s","volume":"261","author":"Ravichandran","year":"1993","journal-title":"Science"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nature01862","article-title":"Crystal Structure of Human Cytochrome P450 2C9 with Bound Warfarin","volume":"424","author":"Williams","year":"2003","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"38091","DOI":"10.1074\/jbc.C400293200","article-title":"The Structure of Human Microsomal Cytochrome P450 3A4 Determined by X-Ray Crystallography to 2.05-A Resolution","volume":"279","author":"Yano","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7614","DOI":"10.1074\/jbc.M511232200","article-title":"Crystal Structure of Human Cytochrome P450 2D6","volume":"281","author":"Rowland","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"14348","DOI":"10.1074\/jbc.M611692200","article-title":"Adaptations for the Oxidation of Polycyclic Aromatic Hydrocarbons Exhibited by the Structure of Human P450 1A2","volume":"282","author":"Sansen","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1093\/mutage\/gel054","article-title":"The Stimulatory Role of Human Cytochrome b5 in the Bioactivation Activities of Human CYP1A2, 2A6 and 2E1: A New Cell Expression System to Study Cytochrome P450-Mediated Biotransformation (a Corrigendum Report on Duarte et al. (2005) Mutagenesis 20, 93\u2013100)","volume":"22","author":"Duarte","year":"2007","journal-title":"Mutagenesis"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/FPC.0b013e32835c2ddf","article-title":"Functional Characterization of Eight Human CYP1A2 Variants: The Role of Cytochrome b5","volume":"23","author":"Palma","year":"2013","journal-title":"Pharmacogenet. Genomics"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1006\/prep.2001.1578","article-title":"Roles of NADPH-P450 Reductase and Apo- and Holo-Cytochrome b5 on Xenobiotic Oxidations Catalyzed by 12 Recombinant Human Cytochrome P450s Expressed in Membranes of Escherichia Coli","volume":"24","author":"Yamazaki","year":"2002","journal-title":"Protein Expr. Purif."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1016\/j.bcp.2003.08.004","article-title":"Effects of Cytochrome b(5) on Drug Oxidation Activities of Human Cytochrome P450 (CYP) 3As: Similarity of CYP3A5 with CYP3A4 but Not CYP3A7","volume":"66","author":"Yamaori","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jsbmb.2014.11.024","article-title":"Cytochrome b5 Modulates Multiple Reactions in Steroidogenesis by Diverse Mechanisms","volume":"151","author":"Storbeck","year":"2015","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/978-3-319-16009-2_10","article-title":"Mechanistic Basis of Electron Transfer to Cytochromes P450 by Natural Redox Partners and Artificial Donor Constructs","volume":"851","author":"Hlavica","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Ortiz de Montellano, P.R. (2015). Cytochrome P450: Structure, Mechanism, and Biochemistry, Springer International Publishing.","DOI":"10.1007\/978-3-319-12108-6"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"20120431","DOI":"10.1098\/rstb.2012.0431","article-title":"Human Cytochromes P450 in Health and Disease","volume":"368","author":"Nebert","year":"2013","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/dna.1987.6.1","article-title":"The P450 Gene Superfamily: Recommended Nomenclature","volume":"6","author":"Nebert","year":"1987","journal-title":"DNA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0165-1161(83)90010-9","article-title":"Revised Methods for the Salmonella Mutagenicity Test","volume":"113","author":"Maron","year":"1983","journal-title":"Mutat. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"503094","DOI":"10.1016\/j.mrgentox.2019.503094","article-title":"A Personally Guided Tour on Some of Our Data with the Ames Assay-A Tribute to Professor Bruce Ames","volume":"846","author":"Rueff","year":"2019","journal-title":"Mutat. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1093\/mutage\/gei029","article-title":"Salmonella\/Human S9 Mutagenicity Test: A Collaborative Study with 58 Compounds","volume":"20","author":"Hakura","year":"2005","journal-title":"Mutagenesis"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2133\/dmpk.DMPK-10-RV-089","article-title":"Role of Biotransformation in Drug-Induced Toxicity: Influence of Intra- and Inter-Species Differences in Drug Metabolism","volume":"26","author":"Baillie","year":"2011","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1124\/jpet.104.067793","article-title":"Metabolism of Thalidomide in Liver Microsomes of Mice, Rabbits, and Humans","volume":"310","author":"Lu","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1073\/pnas.78.4.2545","article-title":"Thalidomide Teratogenesis: Evidence for a Toxic Arene Oxide Metabolite","volume":"78","author":"Gordon","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","first-page":"4752","article-title":"Purified Form of Cytochrome P-450 from Rainbow Trout with High Activity toward Conversion of Aflatoxin B1 to Aflatoxin B1-2,3-Epoxide","volume":"43","author":"Williams","year":"1983","journal-title":"Cancer Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1146\/annurev.pa.34.040194.001031","article-title":"Mechanisms of Aflatoxin Carcinogenesis","volume":"34","author":"Eaton","year":"1994","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_92","first-page":"15","article-title":"Cytochrome P450 Nomenclature","volume":"107","author":"Nelson","year":"1998","journal-title":"Methods Mol. Biol. Clifton N. J."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bbapap.2010.08.008","article-title":"Progress in Tracing the Evolutionary Paths of Cytochrome P450","volume":"1814","author":"Nelson","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.tips.2016.05.006","article-title":"Recent Structural Insights into Cytochrome P450 Function","volume":"37","author":"Guengerich","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1006\/bbrc.1999.1887","article-title":"Forty Years of Cytochrome P450","volume":"266","author":"Omura","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.apsb.2019.12.001","article-title":"The Gut Microbiome: An Orchestrator of Xenobiotic Metabolism","volume":"10","author":"Collins","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/s41586-019-1291-3","article-title":"Mapping Human Microbiome Drug Metabolism by Gut Bacteria and Their Genes","volume":"570","author":"Zimmermann","year":"2019","journal-title":"Nature"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1124\/dmd.115.067504","article-title":"Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics","volume":"44","author":"Selwyn","year":"2016","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1124\/dmd.112.045112","article-title":"Coordinated Regulation of Hepatic Phase I and II Drug-Metabolizing Genes and Transporters Using AhR-, CAR-, PXR-, PPAR\u03b1-, and Nrf2-Null Mice","volume":"40","author":"Aleksunes","year":"2012","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0006-2952(00)00335-X","article-title":"On the Recognition of Mammalian Microsomal Cytochrome P450 Substrates and Their Characteristics: Towards the Prediction of Human P450 Substrate Specificity and Metabolism","volume":"60","author":"Lewis","year":"2000","journal-title":"Biochem. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.bbagen.2014.12.015","article-title":"Access Channels to the Buried Active Site Control Substrate Specificity in CYP1A P450 Enzymes","volume":"1850","author":"Urban","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1124\/pr.117.014407","article-title":"Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption","volume":"70","author":"Nehlig","year":"2018","journal-title":"Pharmacol. Rev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s13530-012-0118-5","article-title":"Gene Expression Analysis Identifies DNA Damage-Related Markers of Benzo[a]Pyrene Exposure in HepG2 Human Hepatocytes","volume":"4","author":"Song","year":"2012","journal-title":"Toxicol. Environ. Health Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1042\/BST20180519","article-title":"Carcinogens and DNA Damage","volume":"46","author":"Barnes","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1097\/FPC.0000000000000150","article-title":"PharmGKB Summary: Pathways of Acetaminophen Metabolism at the Therapeutic versus Toxic Doses","volume":"25","author":"Mazaleuskaya","year":"2015","journal-title":"Pharmacogenet. Genomics"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"213600","DOI":"10.1016\/j.ccr.2020.213600","article-title":"Molecular Probes for Human Cytochrome P450 Enzymes: Recent Progress and Future Perspectives","volume":"427","author":"Wu","year":"2021","journal-title":"Coord. Chem. Rev."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.bbagen.2006.07.003","article-title":"Complex Reactions Catalyzed by Cytochrome P450 Enzymes","volume":"1770","author":"Isin","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.bbrc.2005.09.165","article-title":"The Journey from NADPH-Cytochrome P450 Oxidoreductase to Nitric Oxide Synthases","volume":"338","author":"Masters","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"11374","DOI":"10.1074\/jbc.M807868200","article-title":"Structure and Function of an NADPH-Cytochrome P450 Oxidoreductase in an Open Conformation Capable of Reducing Cytochrome P450","volume":"284","author":"Hamdane","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1038\/embor.2009.82","article-title":"Structure of the Open Conformation of a Functional Chimeric NADPH Cytochrome P450 Reductase","volume":"10","author":"Aigrain","year":"2009","journal-title":"EMBO Rep."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"36628","DOI":"10.1074\/jbc.M109.054304","article-title":"Domain Motion in Cytochrome P450 Reductase: Conformational Equilibria Revealed by NMR and Small-Angle x-Ray Scattering","volume":"284","author":"Ellis","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"755","DOI":"10.3389\/fphar.2017.00755","article-title":"The Hinge Segment of Human NADPH-Cytochrome P450 Reductase in Conformational Switching: The Critical Role of Ionic Strength","volume":"8","author":"Campelo","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Campelo, D., Esteves, F., Brito Palma, B., Costa Gomes, B., Rueff, J., Lautier, T., Urban, P., Truan, G., and Kranendonk, M. (2018). Probing the Role of the Hinge Segment of Cytochrome P450 Oxidoreductase in the Interaction with Cytochrome P450. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123914"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1021\/tx300132k","article-title":"Contributions of Human Enzymes in Carcinogen Metabolism","volume":"25","author":"Rendic","year":"2012","journal-title":"Chem. Res. Toxicol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1124\/dmd.110.035378","article-title":"CYP4F Enzymes Are Responsible for the Elimination of Fingolimod (FTY720), a Novel Treatment of Relapsing Multiple Sclerosis","volume":"39","author":"Jin","year":"2011","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.2174\/15680266113139990110","article-title":"CYP4 Enzymes as Potential Drug Targets: Focus on Enzyme Multiplicity, Inducers and Inhibitors, and Therapeutic Modulation of 20-Hydroxyeicosatetraenoic Acid (20-HETE) Synthase and Fatty Acid \u03c9-Hydroxylase Activities","volume":"13","author":"Edson","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1021\/acs.chemrestox.9b00293","article-title":"Metabolism of Benzalkonium Chlorides by Human Hepatic Cytochromes P450","volume":"32","author":"Seguin","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1124\/jpet.110.175851","article-title":"Genistein, Resveratrol, and 5-Aminoimidazole-4-Carboxamide-1-\u03b2-D-Ribofuranoside Induce Cytochrome P450 4F2 Expression through an AMP-Activated Protein Kinase-Dependent Pathway","volume":"337","author":"Hsu","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_119","first-page":"1","article-title":"Role of Cytochrome P450 Monooxygenase in Carcinogen and Chemotherapeutic Drug Metabolism","volume":"74","author":"Wahlang","year":"2015","journal-title":"Adv. Pharmacol. San Diego Calif"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1158\/1055-9965.EPI-07-2844","article-title":"Extensive Metabolic Activation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Smokers","volume":"17","author":"Stepanov","year":"2008","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.abb.2004.07.035","article-title":"Principles of Covalent Binding of Reactive Metabolites and Examples of Activation of Bis-Electrophiles by Conjugation","volume":"433","author":"Guengerich","year":"2005","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1081\/DMR-120023681","article-title":"PM Frequencies of Major CYPs in Asians and Caucasians","volume":"35","author":"Mizutani","year":"2003","journal-title":"Drug Metab. Rev."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"9057","DOI":"10.1016\/S0021-9258(17)39456-5","article-title":"Purification and Characterization of the Human Liver Cytochromes P-450 Involved in Debrisoquine 4-Hydroxylation and Phenacetin O-Deethylation, Two Prototypes for Genetic Polymorphism in Oxidative Drug Metabolism","volume":"260","author":"Distlerath","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"89","DOI":"10.5487\/TR.2016.32.2.089","article-title":"Cancer Activation and Polymorphisms of Human Cytochrome P450 1B1","volume":"32","author":"Chun","year":"2016","journal-title":"Toxicol. Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.pharmthera.2007.09.004","article-title":"Influence of Cytochrome P450 Polymorphisms on Drug Therapies: Pharmacogenetic, Pharmacoepigenetic and Clinical Aspects","volume":"116","author":"Sim","year":"2007","journal-title":"Pharmacol. Ther."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jsbmb.2016.04.003","article-title":"P450 Oxidoreductase Deficiency: Analysis of Mutations and Polymorphisms","volume":"165","author":"Burkhard","year":"2017","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"580","DOI":"10.3389\/fphar.2017.00580","article-title":"Altered CYP19A1 and CYP3A4 Activities Due to Mutations A115V, T142A, Q153R and P284L in the Human P450 Oxidoreductase","volume":"8","author":"Udhane","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3389\/fphar.2020.00299","article-title":"The Role of the FMN-Domain of Human Cytochrome P450 Oxidoreductase in Its Promiscuous Interactions With Structurally Diverse Redox Partners","volume":"11","author":"Esteves","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Esteves, F., Urban, P., Rueff, J., Truan, G., and Kranendonk, M. (2020). Interaction Modes of Microsomal Cytochrome P450s with Its Reductase and the Role of Substrate Binding. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186669"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/clpt.2008.302","article-title":"Impact of Infectious and Inflammatory Disease on Cytochrome P450\u2013Mediated Drug Metabolism and Pharmacokinetics","volume":"85","author":"Morgan","year":"2009","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_131","unstructured":"Wen, X. (2017). Drug Metabolism in Diseases, Elsevier."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1124\/mol.110.064899","article-title":"Role of Epigenetic Mechanisms in Differential Regulation of the Dioxin-Inducible Human CYP1A1 and CYP1B1 Genes","volume":"78","author":"Beedanagari","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1124\/dmd.109.027680","article-title":"MicroRNAs Regulate CYP3A4 Expression via Direct and Indirect Targeting","volume":"37","author":"Pan","year":"2009","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Dannenberg, L.O., and Edenberg, H.J. (2006). Epigenetics of Gene Expression in Human Hepatoma Cells: Expression Profiling the Response to Inhibition of DNA Methylation and Histone Deacetylation. BMC Genomics, 7.","DOI":"10.1186\/1471-2164-7-181"},{"key":"ref_135","first-page":"8623","article-title":"Methylation of Cytochrome P4501A1 Promoter in the Lung Is Associated with Tobacco Smoking","volume":"63","author":"Anttila","year":"2003","journal-title":"Cancer Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"9090","DOI":"10.1158\/0008-5472.CAN-06-1403","article-title":"MicroRNA Regulates the Expression of Human Cytochrome P450 1B1","volume":"66","author":"Tsuchiya","year":"2006","journal-title":"Cancer Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.bcp.2009.11.015","article-title":"Human CYP2E1 Is Regulated by MiR-378","volume":"79","author":"Mohri","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.bbrc.2014.02.024","article-title":"MicroRNA-34a Is Associated with Expression of Key Hepatic Transcription Factors and Cytochromes P450","volume":"445","author":"Lamba","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"625","DOI":"10.2217\/pgs.10.59","article-title":"The Past, Present and Future of Pharmacoepigenomics","volume":"11","author":"Gomez","year":"2010","journal-title":"Pharmacogenomics"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Ortiz de Montellano, P.R. (2015). Cytochrome P450, Springer International Publishing.","DOI":"10.1007\/978-3-319-12108-6"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"13422","DOI":"10.1039\/C9CC05904K","article-title":"Probing Protein-Protein and Protein-Substrate Interactions in the Dynamic Membrane-Associated Ternary Complex of Cytochromes P450, b5, and Reductase","volume":"55","author":"Gentry","year":"2019","journal-title":"Chem. Commun. Camb. Engl."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.1742-7843.2009.00405.x","article-title":"The Effect of Infliximab on Hepatic Cytochrome P450 and Pharmacokinetics of Verapamil in Rats with Pre-Adjuvant Arthritis: A Drug-Disease and Drug-Drug Interaction","volume":"105","author":"Ling","year":"2009","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/jbt.20180","article-title":"Mechanisms of Cytochrome P450 Induction","volume":"21","author":"Tompkins","year":"2007","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s00204-008-0332-8","article-title":"Inhibition and Induction of Human Cytochrome P450 Enzymes: Current Status","volume":"82","author":"Pelkonen","year":"2008","journal-title":"Arch. Toxicol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.abb.2012.07.015","article-title":"Accumulation of Cytochrome P450 Induced by Proteasome Inhibition during Cardiac Ischemia","volume":"527","author":"Ishihara","year":"2012","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1517\/17425250903012360","article-title":"Phosphorylation and Protein-Protein Interactions in PXR-Mediated CYP3A Repression","volume":"5","author":"Pondugula","year":"2009","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"100177","DOI":"10.1016\/j.jhepr.2020.100177","article-title":"Our Emerging Understanding of the Roles of Long Non-Coding RNAs in Normal Liver Function, Disease, and Malignancy","volume":"3","author":"Mahpour","year":"2021","journal-title":"JHEP Rep. Innov. Hepatol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1111\/j.1440-1746.2009.05800.x","article-title":"Coordinate Regulation of Metabolic Enzymes and Transporters by Nuclear Transcription Factors in Human Liver Disease","volume":"24","author":"Congiu","year":"2009","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.bcp.2009.08.008","article-title":"Constitutive Androstane Receptor Transcriptionally Activates Human CYP1A1 and CYP1A2 Genes through a Common Regulatory Element in the 5\u2019-Flanking Region","volume":"79","author":"Yoshinari","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1124\/jpet.106.107573","article-title":"Induction of Human CYP2A6 Is Mediated by the Pregnane X Receptor with Peroxisome Proliferator-Activated Receptor-Gamma Coactivator 1alpha","volume":"319","author":"Itoh","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"6043","DOI":"10.1074\/jbc.274.10.6043","article-title":"The Repressed Nuclear Receptor CAR Responds to Phenobarbital in Activating the Human CYP2B6 Gene","volume":"274","author":"Sueyoshi","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"14146","DOI":"10.1074\/jbc.M212482200","article-title":"A Novel Distal Enhancer Module Regulated by Pregnane X Receptor\/Constitutive Androstane Receptor Is Essential for the Maximal Induction of CYP2B6 Gene Expression","volume":"278","author":"Wang","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nrd753","article-title":"PXR, CAR and Drug Metabolism","volume":"1","author":"Willson","year":"2002","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1124\/mol.105.021220","article-title":"A Common Regulatory Region Functions Bidirectionally in Transcriptional Activation of the Human CYP1A1 and CYP1A2 Genes","volume":"69","author":"Ueda","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/humu.21132","article-title":"Analysis of Human CYP1A1 and CYP1A2 Genes and Their Shared Bidirectional Promoter in Eight World Populations","volume":"31","author":"Jiang","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.clpt.2006.01.008","article-title":"Female Sex and Oral Contraceptive Use Accelerate Nicotine Metabolism","volume":"79","author":"Benowitz","year":"2006","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1124\/dmd.107.016568","article-title":"Human CYP2A6 Is Induced by Estrogen via Estrogen Receptor","volume":"35","author":"Higashi","year":"2007","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"567","DOI":"10.2174\/138920009789375397","article-title":"The Transcriptional Regulation of the Human CYP2C Genes","volume":"10","author":"Chen","year":"2009","journal-title":"Curr. Drug Metab."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"206","DOI":"10.3389\/fgene.2012.00206","article-title":"Molecular Mechanisms of Genetic Variation and Transcriptional Regulation of CYP2C19","volume":"3","author":"Helsby","year":"2012","journal-title":"Front. Genet."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1124\/dmd.111.042259","article-title":"Simultaneous Absolute Protein Quantification of Transporters, Cytochromes P450, and UDP-Glucuronosyltransferases as a Novel Approach for the Characterization of Individual Human Liver: Comparison with MRNA Levels and Activities","volume":"40","author":"Ohtsuki","year":"2012","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"508","DOI":"10.2174\/138920009788898000","article-title":"Transcriptional Regulation of Cytochrome P450 Genes by the Nuclear Receptor Hepatocyte Nuclear Factor 4-Alpha","volume":"10","author":"Jover","year":"2009","journal-title":"Curr. Drug Metab."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1124\/mol.65.2.326","article-title":"Identification of a Novel Polymorphic Enhancer of the Human CYP3A4 Gene","volume":"65","author":"Matsumura","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_163","first-page":"2473","article-title":"Inferring Statin-Induced Gene Regulatory Relationships in Primary Human Hepatocytes","volume":"27","author":"Wollnik","year":"2011","journal-title":"Bioinforma. Oxf. Engl."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1124\/mol.104.008169","article-title":"Transcriptional Regulation of the Human Hepatic CYP3A4: Identification of a New Distal Enhancer Region Responsive to CCAAT\/Enhancer-Binding Protein Beta Isoforms (Liver Activating Protein and Liver Inhibitory Protein)","volume":"67","author":"Castell","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1124\/mol.63.5.1180","article-title":"Transcriptional Regulation of Human CYP3A4 Basal Expression by CCAAT Enhancer-Binding Protein Alpha and Hepatocyte Nuclear Factor-3 Gamma","volume":"63","author":"Bort","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.cell.2005.12.022","article-title":"Protein Sensors for Membrane Sterols","volume":"124","author":"Goldstein","year":"2006","journal-title":"Cell"},{"key":"ref_167","first-page":"104681","article-title":"Human CYP1A1 Inhibition by Flavonoids","volume":"62","author":"Govezensky","year":"2020","journal-title":"Toxicol. Vitro Int. J. Publ. Assoc. BIBRA"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1080\/03602532.2016.1206562","article-title":"Effects of Soy Containing Diet and Isoflavones on Cytochrome P450 Enzyme Expression and Activity","volume":"48","author":"Ronis","year":"2016","journal-title":"Drug Metab. Rev."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0006-2952(98)00372-4","article-title":"Decrease in Hepatic Cytochrome P450 after Interleukin-2 Immunotherapy","volume":"57","author":"Elkahwaji","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1016\/j.bcp.2004.06.003","article-title":"Determination of Interleukin-4-Responsive Region in the Human Cytochrome P450 2E1 Gene Promoter","volume":"68","author":"Garlatti","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1067\/mcp.2000.103860","article-title":"In Vivo Effects of Interleukin-10 on Human Cytochrome P450 Activity","volume":"67","author":"Gorski","year":"2000","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1124\/dmd.114.061317","article-title":"Establishment of a Hepatocyte-Kupffer Cell Coculture Model for Assessment of Proinflammatory Cytokine Effects on Metabolizing Enzymes and Drug Transporters","volume":"43","author":"Nguyen","year":"2015","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1053\/jhep.2000.8532","article-title":"Hepatic Cytochrome P450 Down-Regulation during Aseptic Inflammation in the Mouse Is Interleukin 6 Dependent","volume":"32","author":"Siewert","year":"2000","journal-title":"Hepatol. Baltim. Md."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1124\/dmd.114.061093","article-title":"Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine","volume":"43","author":"Shah","year":"2015","journal-title":"Drug Metab. Dispos."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"7492","DOI":"10.1158\/1078-0432.CCR-06-0023","article-title":"Transcriptional Repression of Hepatic Cytochrome P450 3A4 Gene in the Presence of Cancer","volume":"12","author":"Charles","year":"2006","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_176","first-page":"524","article-title":"Hepatic and Central Nervous System Cytochrome P450 Are Down-Regulated during Lipopolysaccharide-Evoked Localized Inflammation in Brain","volume":"294","author":"Renton","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.taap.2006.03.012","article-title":"The Regulation of Cytochrome P450 2E1 during LPS-Induced Inflammation in the Rat","volume":"216","author":"Abdulla","year":"2006","journal-title":"Toxicol. Appl. Pharmacol."}],"container-title":["Journal of Xenobiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-4713\/11\/3\/7\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:20:47Z","timestamp":1760163647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-4713\/11\/3\/7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,22]]},"references-count":177,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["jox11030007"],"URL":"https:\/\/doi.org\/10.3390\/jox11030007","relation":{},"ISSN":["2039-4713"],"issn-type":[{"value":"2039-4713","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,22]]}}}