Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

  • Guengerich, F. Peter (Department of Biochemistry, Vanderbilt University School of Medicine)
  • Received : 2020.05.22
  • Accepted : 2020.06.11
  • Published : 2021.01.15
⟨ Previous Next ⟩

Abstract

The history of drug metabolism began in the 19th Century and developed slowly. In the mid-20th Century the relationship between drug metabolism and toxicity became appreciated, and the roles of cytochrome P450 (P450) enzymes began to be defined in the 1960s. Today we understand much about the metabolism of drugs and many aspects of safety assessment in the context of a relatively small number of human P450s. P450s affect drug toxicity mainly by either reducing exposure to the parent molecule or, in some cases, by converting the drug into a toxic entity. Some of the factors involved are enzyme induction, enzyme inhibition (both reversible and irreversible), and pharmacogenetics. Issues related to drug toxicity include drug-drug interactions, drug-food interactions, and the roles of chemical moieties of drug candidates in drug discovery and development. The maturation of the field of P450 and drug toxicity has been facilitated by advances in analytical chemistry, computational capability, biochemistry and enzymology, and molecular and cell biology. Problems still arise with P450s and drug toxicity in drug discovery and development, and in the pharmaceutical industry the interaction of scientists in medicinal chemistry, drug metabolism, and safety assessment is critical for success.

Keywords

Acknowledgement

This work was supported by United States National Institutes of Health grant R01 GM118122. Thanks are extended to K. Trisler for assistance in preparation of the manuscript and to Y. Tateishi for the paradigm shown in Fig. 4. This review is dedicated to an old friend, Dr. Anthony Y. H. Lu, who shared my enthusiasm of P450 research for many years and introduced me to many applications in the pharmaceutical industry, and to the memory of our mutual mentor, Professor Minor J. Coon (1921-2018), who taught us both well.

References

  1. Walgren JL, Mitchell MD, Thompson DC (2005) Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 35:325-361 https://doi.org/10.1080/10408440590935620
  2. Borzelleca JF (2000) Profiles in toxicology-Paracelsus: herald of modern toxicology. Toxicol Sci 53:2-4 https://doi.org/10.1093/toxsci/53.1.2
  3. Wohler F (1828) uber kunstliche Bildung des Harnstoffs. Annal Physik Chemie 88:253-256 https://doi.org/10.1002/andp.18280880206
  4. Bachmann C, Bickel MH (1985) History of drug metabolism: the first half of the 20th century. Drug Metab Rev 16:185-253. https://doi.org/10.3109/03602538508991435
  5. Guengerich FP (2018) Introduction and historical perspective. In: Guengerich FP (ed) Biotransformation, vol 10. Comprehensive toxicology (McQueen CA, Series ed), 3rd edn. Elsevier, Oxford, pp 1-7
  6. Ambrose AM, Sherwin CP (1933) Detoxication mechanisms. Annu Rev Biochem 2:377-396. https://doi.org/10.1146/annurev.bi.02.070133.002113
  7. Handler P, Perlzweig WA (1945) Detoxication mechanisms. Annu Rev Biochem 14:617-642. https://doi.org/10.1146/annurev.bi.14.070145.003153
  8. Neuberger A, Smith RL (1983) Richard Tecwyn Williams: the man, his work, his impact. Drug Metab Rev 14:559-607. https://doi.org/10.3109/03602538308991399
  9. Williams RT (1947) Detoxication mechanisms, 1st edn. Wiley, New York
  10. Brodie BB, Gillette JR, LaDu BN (1958) Enzymatic metabolism of drugs and other foreign compounds. Annu Rev Biochem 27:427-454 https://doi.org/10.1146/annurev.bi.27.070158.002235
  11. Remmer H (1959) The acceleration of evipan oxidation and the demethylation of methylaminopyrine by barbiturates. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 237:296-307 https://doi.org/10.1007/BF00244737
  12. Remmer H (1957) The acceleration of evipan oxidation and the demethylation of methylaminopyrine by barbiturates. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 237:296-307
  13. Conney AH, Miller EC, Miller JA (1956) The metabolism of methylated aminoazo dyes. V. Evidence for induction of enzyme synthesis in the rat by 3-methylcholanthrene. Cancer Res 16:450-459
  14. Garfinkel D (1958) Studies on pig liver microsomes. I. Enzymic and pigment composition of different microsomal fractions. Arch Biochem Biophys 77:493-509 https://doi.org/10.1016/0003-9861(58)90095-X
  15. Klingenberg M (1958) Pigments of rat liver microsomes. Arch Biochem Biophys 75:376-386 https://doi.org/10.1016/0003-9861(58)90436-3
  16. Omura T, Sato R (1962) A new cytochrome in liver microsomes. J Biol Chem 237:1375-1376
  17. Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239:2370-2378 https://doi.org/10.1016/S0021-9258(20)82244-3
  18. Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. II. Solubilization, purification, and properties. J Biol Chem 239:2379-2385 https://doi.org/10.1016/S0021-9258(20)82245-5
  19. Cooper DY, Levine S, Narasimhulu S, Rosenthal O, Estabrook RW (1965) Photochemical action spectrum of the terminal oxidase of mixed function oxidase systems. Science 147:400-402 https://doi.org/10.1126/science.147.3656.400
  20. Speirs AL (1962) Thalidomide and congenital abnormalities. Lancet 1:303-305 https://doi.org/10.1016/S0140-6736(02)98913-0
  21. Williams RT (1963) Teratogenic effects of thalidomide and related substances. Lancet 1:723-724. https://doi.org/10.1016/s0140-6736(63)91486-7
  22. Schumacher H, Smith RL, Williams RT (1965) The metabolism of thalidomide: The fate of thalidomide and some of its hydrolysis products in various species. Br J Pharmacol Chemother 25:338-351 https://doi.org/10.1111/j.1476-5381.1965.tb02054.x
  23. Gordon GB, Spielberg SP, Blake DA, Balasubramanian V (1981) Thalidomide teratogenesis: evidence for a toxic arene oxide metabolite. Proc Natl Acad Sci USA 78:2545-2548 https://doi.org/10.1073/pnas.78.4.2545
  24. Yamazaki H, Suemizu H, Kazuki Y, Oofusa K, Kuribayashi S, Shimizu M, Ninomiya S, Horie T, Shibata N, Guengerich FP (2016) Assessment of protein binding of 5-hydroxythalidomide bioactivated in humanized mice with human P450 3A-chromosome or hepatocytes by two-dimensional electrophoresis/accelerator mass spectrometry. Chem Res Toxicol 29:1279-1281. https://doi.org/10.1021/acs.chemrestox.6b00210
  25. Chowdhury G, Shibata N, Yamazaki H, Guengerich FP (2014) Human cytochrome P450 oxidation of 5-hydroxythalidomide and pomalidomide, an amino analogue of thalidomide. Chem Res Toxicol 27:147-156. https://doi.org/10.1021/tx4004215
  26. Yamazaki H, Suemizu H, Shimizu M, Igaya S, Shibata N, Nakamura M, Chowdhury G, Guengerich FP (2012) In vivo formation of dihydroxylated and glutathione conjugate metabolites derived from thalidomide and 5-hydroxythalidomide in humanized TK-NOG mice. Chem Res Toxicol 25:274-276. https://doi.org/10.1021/tx300009j
  27. Yamazaki H, Suemizu H, Igaya S, Shimizu M, Shibata N, Nakamura M, Chowdhury G, Guengerich FP (2011) In vivo formation of a glutathione conjugate derived from thalidomide in humanized uPA-NOG mice. Chem Res Toxicol 24:287-289. https://doi.org/10.1021/tx200005g
  28. Chowdhury G, Murayama N, Okada Y, Uno Y, Shimizu M, Shibata N, Guengerich FP, Yamazaki H (2010) Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate. Chem Res Toxicol 23:1018-1024. https://doi.org/10.1021/tx900367p
  29. Wani TH, Chakrabarty A, Shibata N, Yamazaki H, Guengerich FP, Chowdhury G (2017) The dihydroxy metabolite of the teratogen thalidomide causes oxidative DNA damage. Chem Res Toxicol 30:1622-1628. https://doi.org/10.1021/acs.chemrestox.7b00127
  30. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (2010) Identification of a primary target of thalidomide teratogenicity. Science 327:1345-1350 https://doi.org/10.1126/science.1177319
  31. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiodt FV, Ostapowicz G, Shakil AO, Lee WM (2005) Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 42:1364-1372 https://doi.org/10.1002/hep.20948
  32. Potter WZ, Davis DC, Mitchell JR, Jollow DJ, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. III. Cytochrome P-450-mediated covalent binding in vitro. J Exp Pharmacol Ther 187:203-210
  33. Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Exp Pharmacol Therap 187:211-217
  34. Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Exp Pharmacol Ther 187:185-194
  35. Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Exp Pharmacol Ther 187:195-202
  36. Patten CJ, Thomas PE, Guy RL, Lee M, Gonzalez FJ, Guengerich FP, Yang CS (1993) Cytochrome P450 enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics. Chem Res Toxicol 6:511-518 https://doi.org/10.1021/tx00034a019
  37. Lee SST, Buters JTM, Pineau T, Fernandez-Salguero P, Gonzalez FJ (1996) Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 271:12063-12067 https://doi.org/10.1074/jbc.271.20.12063
  38. Zaher H, Buters JT, Ward JM, Bruno MK, Lucas AM, Stern ST, Cohen SD, Gonzalez FJ (1998) Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol Appl Pharmacol 152:193-199 https://doi.org/10.1006/taap.1998.8501
  39. Dahlin DC, Nelson SD (1982) Synthesis, decomposition kinetics, and preliminary toxicological studies of pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetaminophen. J Med Chem 25:885-886 https://doi.org/10.1021/jm00350a001
  40. Dahlin DC, Miwa GT, Lu AYH, Nelson SD (1984) N-Acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 81:1327-1331 https://doi.org/10.1073/pnas.81.5.1327
  41. Qiu Y, Benet LZ, Burlingame AL (1998) Identification of the hepatic protein targets of reactive metabolites of acetaminophen in vivo in mice using two-dimensional gel electrophoresis and mass spectrometry. J Biol Chem 273:17940-17953 https://doi.org/10.1074/jbc.273.28.17940
  42. Streeter AJ, Bjorge SM, Axworthy DB, Nelson SD, Baillie TA (1984) The microsomal metabolism and site of covalent binding to protein of 3'-hydroxyacetanilide, a nonhepatotoxic positional isomer of acetaminophen. Drug Metab Dispos 12:565-576
  43. Jaeschke H (2008) Innate immunity and acetaminophen-induced liver injury: why so many controversies? Hepatology 48:699-701. https://doi.org/10.1002/hep.22556
  44. Harrill AH, Watkins PB, Su S, Ross PK, Harbourt DE, Stylianou IM, Boorman GA, Russo MW, Sackler RS, Harris SC, Smith PC, Tennant R, Bogue M, Paigen K, Harris C, Contractor T, Wiltshire T, Rusyn I, Threadgill DW (2009) Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res 19:1507-1515 https://doi.org/10.1101/gr.090241.108
  45. Court MH, Peter I, Hazarika S, Vasiadi M, Gresenblatt DJ, Lee WM, Acute Liver Failure Study Group (2014) Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure. Drug Metab Dispos 42:28-32. https://doi.org/10.1124/dmd.113.053546
  46. Testa B, Jenner P (1976) Drug metabolism: chemical and biochemical aspects. Marcel Dekker, New York
  47. Williams RT (1959) Detoxication mechanisms, 2nd edn. Wiley, New York
  48. Nebert DW (1989) The Ah locus: genetic differences in toxicity, cancer, mutation, and birth defects. Crit Rev Toxicol 20:153-174 https://doi.org/10.3109/10408448909017908
  49. Robinson JR, Nebert DW (1974) Genetic expression of aryl hydrocarbon hydroxylase induction. Presence or absence of association with zoxazolamine, diphenylhydantoin, and hexobarbital metabolism. Mol Pharmacol 10:484-493
  50. Shichi H, Gaasterland DE, Jensen NM, Nebert DW (1978) Ah locus: genetic differences in susceptibility to cataracts induced by acetaminophen. Science 200:539-541 https://doi.org/10.1126/science.644313
  51. Mitchell JR, Potter WZ, Hinson JA, Jollow DJ (1974) Hepatic necrosis caused by furosemide. Nature 251:508-511 https://doi.org/10.1038/251508a0
  52. Wirth PJ, Bettis CJ, Nelson WL (1976) Microsomal metabolism of furosemide evidence for the nature of the reactive intermediate involved in covalent binding. Mol Pharmacol 12:759-768
  53. McMurtry RJ, Mitchell JR (1977) Renal and hepatic necrosis after metabolic activation of 2-substituted furans and thiophenes, including furosemide and cephaloridine. Toxicol Appl Pharmacol 42:285-300 https://doi.org/10.1016/0041-008X(77)90005-9
  54. Yamazaki H, Shibata A, Suzuki M, Nakajima M, Shimada N, Guengerich FP, Yokoi T (1999) Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes. Drug Metab Dispos 27:1260-1266
  55. Kassahun K, Pearson PG, Tang W, McIntosh I, Leung K, Elmore C, Dean D, Wang R, Doss G, Baillie TA (2001) Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem Res Toxicol 14:62-70 https://doi.org/10.1021/tx000180q
  56. Reddy VB, Karanam BV, Gruber WL, Wallace MA, Vincent SH, Franklin RB, Baillie TA (2005) Mechanistic studies on the metabolic scission of thiazolidinedione derivatives to acyclic thiols. Chem Res Toxicol 18:880-888 https://doi.org/10.1021/tx0500373
  57. Isin EM, Guengerich FP (2007) Complex reactions catalyzed by cytochrome P450 enzymes. Biochim Biophys Acta 1770:314-329. https://doi.org/10.1016/j.bbagen.2006.07.003
  58. Miller JA (1970) Carcinogenesis by chemicals: an overview. G.H.A Clowes memorial lecture. Cancer Res 30:559-576
  59. Ames BN, Durston WE, Yamasaki E, Lee FD (1973) Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci USA 70:2281-2285 https://doi.org/10.1073/pnas.70.8.2281
  60. Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA (2004) Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 17:3-16 https://doi.org/10.1021/tx034170b
  61. Hildebrandt A, Remmer H, Estabrook RW (1968) Cytochrome P-450 of liver microsomes: one pigment or many. Biochem Biophys Res Commun 30:607-612 https://doi.org/10.1016/0006-291X(68)90555-X
  62. Sladek NE, Mannering GJ (1969) Induction of drug metabolism. II. Qualitative differences in the microsomal N-demethylating systems stimulated by polycyclic hydrocarbons and by phenobarbital. Mol Pharmacol 5:186-199
  63. Gillette JR, Conney AH, Cosmides GJ, Estabrook RW, Fouts JR, Mannering GJ (1969) Microsomes and drug oxidations. Academic Press, New York
  64. Lu AYH, Coon MJ (1968) Role of hemoprotein P-450 in fatty acid w-hydroxylation in a soluble enzyme system from liver microsomes. J Biol Chem 243:1331-1332 https://doi.org/10.1016/S0021-9258(19)56992-7
  65. Lu AYH, Strobel HW, Coon MJ (1969) Hydroxylation of benzphetamine and other drugs by a solubilized form of cytochrome P-450 from liver microsomes: lipid requirement for drug demethylation. Biochem Biophys Res Commun 36:545-551 https://doi.org/10.1016/0006-291X(69)90339-8
  66. Haugen DA, van der Hoeven TA, Coon MJ (1975) Purified liver microsomal cytochrome P-450: separation and characterization of multiple forms. J Biol Chem 250:3567-3570 https://doi.org/10.1016/S0021-9258(19)41552-4
  67. Imai Y, Sato R (1974) A gel-electrophoretically homogeneous preparation of cytochrome P-450 from liver microsomes of phenobarbital-pretreated rabbits. Biochem Biophys Res Commun 60:8-14 https://doi.org/10.1016/0006-291X(74)90164-8
  68. Johnson EF, Muller-Eberhard U (1977) Purification of the major cytochrome P-450 of liver microsomes from rabbits treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Biochem Biophys Res Commun 76:652-659 https://doi.org/10.1016/0006-291X(77)91550-9
  69. Ryan D, Lu AYH, Kawalek J, West SB, Levin W (1975) Highly purified cytochrome P-448 and P-450 from rat liver microsomes. Biochem Biophys Res Commun 64:1134-1141 https://doi.org/10.1016/0006-291X(75)90812-8
  70. Guengerich FP (1978) Separation and purification of multiple forms of microsomal cytochrome P-450. Partial characterization of three apparently homogeneous cytochromes P-450 prepared from livers of phenobarbital- and 3-methylcholanthrene-treated rats. J Biol Chem 253:7931-7939 https://doi.org/10.1016/S0021-9258(17)34461-7
  71. Guengerich FP (1977) Separation and purification of multiple forms of microsomal cytochrome P-450. Activities of different forms of cytochrome P-450 towards several compounds of environmental interest. J Biol Chem 252:3970-3979 https://doi.org/10.1016/S0021-9258(17)40345-0
  72. Thomaszewski JE, Jerina DM, Levin W, Conney AH (1976) A highly senstivive radiometric assay for zoxazolamine hydroxylation by liver microsomal cytochrome P-450 and P-448: properties of the membrane-bound and purified reconstituted system. Arch Biochem Biophys 176:788-798 https://doi.org/10.1016/0003-9861(76)90223-X
  73. Beaune P, Dansette P, Flinois JP, Columelli S, Mansuy D, Leroux J-P (1979) Partial purification of human liver cytochrome P-450. Biochem Biophys Res Commun 88:826-832 https://doi.org/10.1016/0006-291X(79)91482-7
  74. Kitada M, Kamataki T (1979) Partial purification and properties of cytochrome P450 from homogenates of human fetal livers. Biochem Pharmacol 28:793-797 https://doi.org/10.1016/0006-2952(79)90360-5
  75. Wang P, Mason PS, Guengerich FP (1980) Purification of human liver cytochrome P-450 and comparison to the enzyme isolated from rat liver. Arch Biochem Biophys 199:206-219 https://doi.org/10.1016/0003-9861(80)90274-X
  76. Wang PP, Beaune P, Kaminsky LS, Dannan GA, Kadlubar FF, Larrey D, Guengerich FP (1983) Purification and characterization of six cytochrome P-450 isozymes from human liver microsomes. Biochemistry 22:5375-5383 https://doi.org/10.1021/bi00292a019
  77. Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2:584-586
  78. Tucker GT, Silas JH, Iyun AO, Lennard MS, Smith AJ (1977) Polymorphic hydroxylation of debrisoquine. Lancet 2:718
  79. Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ (1979) Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 16:183-187 https://doi.org/10.1007/BF00562059
  80. Mukhopadhyay R (2012) Human cytochrome P450s: the work of Frederick Peter Guengerich. J Biol Chem 287:15798-15800. https://doi.org/10.1074/jbc.O112.000003
  81. Distlerath LM, Reilly PE, Martin MV, Davis GG, Wilkinson GR, Guengerich FP (1985) 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. J Biol Chem 260:9057-9067 https://doi.org/10.1016/S0021-9258(17)39456-5
  82. Shimada T, Misono KS, Guengerich FP (1986) Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism. Purification and characterization of two similar forms involved in the reaction. J Biol Chem 261:909-921 https://doi.org/10.1016/S0021-9258(17)36183-5
  83. Guengerich FP, Martin MV, Beaune PH, Kremers P, Wolff T, Waxman DJ (1986) Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J Biol Chem 261:5051-5060 https://doi.org/10.1016/S0021-9258(19)89213-X
  84. Barnes HJ, Arlotto MP, Waterman MR (1991) Expression and enzymatic activity of recombinant cytochrome P450 17α-hydroxylase in Escherichia coli. Proc Natl Acad Sci USA 88:5597-5601 https://doi.org/10.1073/pnas.88.13.5597
  85. Li YC, Chiang JYL (1991) The expression of a catalytically active cholesterol 7α-hydroxylase cytochrome P-450 in Escherichia coli. J Biol Chem 266:19186-19191 https://doi.org/10.1016/S0021-9258(18)54980-2
  86. Larson JR, Coon MJ, Porter TD (1991) Purification and properties of a shortened form of cytochrome P-450 2E1: deletion of the NH2-terminal membrane-insertion signal peptide does not alter the catalytic activities. Proc Natl Acad Sci USA 88:9141-9145 https://doi.org/10.1073/pnas.88.20.9141
  87. Wang RW, Kari PH, Lu AY, Thomas PE, Guengerich FP, Vyas KP (1991) Biotransformation of lovastatin. IV. Identification of cytochrome P450 3A proteins as the major enzymes responsible for the oxidative metabolism of lovastatin in rat and human liver microsomes. Arch Biochem Biophys 290:355-361 https://doi.org/10.1016/0003-9861(91)90551-S
  88. Waxman DJ, Attisano C, Guengerich FP, Lapenson DP (1988) Human liver microsomal steroid metabolism: identification of the major microsomal steroid hormone 6β-hydroxylase cytochrome P-450 enzyme. Arch Biochem Biophys 263:424-436 https://doi.org/10.1016/0003-9861(88)90655-8
  89. Shimada T, Iwasaki M, Martin MV, Guengerich FP (1989) Human liver microsomal cytochrome P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA 1535/pSK1002. Cancer Res 49:3218-3228
  90. Yun CH, Okerholm RA, Guengerich FP (1993) Oxidation of the antihistaminic drug terfenadine in human liver microsomes. Role of cytochrome P-450 3A(4) in N-dealkylation and C-hydroxylation. Drug Metab Dispos 21:403-409
  91. Garcia MPL, Dansette PM, Valadon P, Amar C, Beaune PH, Guengerich FP, Mansuy D (1993) Human-liver cytochromes P-450 expressed in yeast as tools for reactive-metabolite formation studies. Oxidative activation of tienilic acid by cytochromes P-450 2C9 and 2C10. Eur J Biochem 213:223-232 https://doi.org/10.1111/j.1432-1033.1993.tb17752.x
  92. Palmer CNA, Hsu MH, Griffin KJ, Raucy JL, Johnson EF (1998) Peroxisome proliferator activated receptor-a expression in human liver. Mol Pharmacol 53:14-22 https://doi.org/10.1124/mol.53.1.14
  93. Kliewer SA (2015) Nuclear receptor PXR: discovery of a pharmaceutical anti-target. J Clin Invest 125:1388-1389. https://doi.org/10.1172/jci81244
  94. Davis CD, Adamson RH, Snyderwine EG (1993) Studies on the mutagenic activation of heterocylic amines by cynomolgus monkey, rat and human microsomes show that cynomolgus monkeys have a low capacity to N-oxidize the quinoxaline-type heterocyclic amines. Cancer Lett 73:95-104 https://doi.org/10.1016/0304-3835(93)90250-D
  95. Hosseinpour F, Wikvall K (2000) Porcine microsomal vitamin D3 25-hydroxylase (CYP2D25)-catalytic properties, tissue distribution, and comparison with human CYP2D6. J Biol Chem 275:34650-34655 https://doi.org/10.1074/jbc.M004185200
  96. Hiroi T, Chow T, Imaoka S, Funae Y (2002) Catalytic specificity of CYP2D isoforms in rat and human. Drug Metab Dispos 30:970-976 https://doi.org/10.1124/dmd.30.9.970
  97. Baillie TA, Cayen MN, Fouda H, Gerson RJ, Green JD, Grossman SJ, Klunk LJ, LeBlanc B, Perkins DG, Shipley LA (2002) Drug metabolites in safety testing. Toxicol Appl Pharmacol 182:188-196 https://doi.org/10.1006/taap.2002.9440
  98. Smith DA, Obach RS (2005) Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing. Drug Metab Dispos 33:1409-1417 https://doi.org/10.1124/dmd.105.005041
  99. Guengerich FP (2009) Introduction: human metabolites in safety testing (MIST) issue. Chem Res Toxicol 22:237-238. https://doi.org/10.1021/tx900003k
  100. Kamataki T, Maeda K, Yamazoe Y, Nagai T, Kato R (1982) Evidence for the involvement of multiple forms of cytochrome P-450 in the occurrence of sex-related differences of drug metabolism in the rat. Life Sci 31:2603-2610 https://doi.org/10.1016/0024-3205(82)90735-4
  101. Waxman DJ, Dannan GA, Guengerich FP (1985) Regulation of rat hepatic cytochrome P-450: age-dependent expression, hormonal imprinting, and xenobiotic inducibility of sex-specific isoenzymes. Biochemistry 24:4409-4417 https://doi.org/10.1021/bi00337a023
  102. Dannan GA, Guengerich FP, Waxman DJ (1986) Hormonal regulation of rat liver microsomal enzymes. Role of gonadal steroids in programming, maintenance, and suppression of Δ4-steroid 5α-reductase, flavin-containing monooxygenase, and sex-specific cytochromes P-450. J Biol Chem 261:10728-10735 https://doi.org/10.1016/S0021-9258(18)67446-0
  103. Yang X, Zhang B, Molony C, Chudin E, Hao K, Zhu J, Gaedigk A, Suver C, Zhong H, Leeder JS, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich RG, Slatter JG, Schadt EE, Kasarskis A, Lum PY (2010) Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res 20:1020-1036. https://doi.org/10.1101/gr.103341.109
  104. Su H, Boulton DW, Barros A, Wang LF, Cao K, Bonacorsi SJ, Iyer RA, Humphreys WG, Christopher LJ (2012) Characterization of the in vitro and in vivo metabolism and disposition and cytochrome P450 inhibition/induction profile of saxagliptin in human. Drug Metab Dispos 40:1345-1356. https://doi.org/10.1124/dmd.112.045450
  105. Czerwinski M, McLemore TL, Philpot RM, Nhamburo PT, Korzekwa K, Gelboin HV, Gonzalez FJ (1991) Metabolic activation of 4-ipomeanol by complementary DNA-expressed human cytochromes P-450: evidence for species-specific metabolism. Cancer Res 51:4636-4638
  106. Turesky RJ, Constable A, Richoz J, Varga N, Markovic J, Martin MV, Guengerich FP (1998) Activation of heterocyclic aromatic amines by rat and human liver microsomes and by purified rat and human cytochrome P450 1A2. Chem Res Toxicol 11:925-936. https://doi.org/10.1021/tx980022n
  107. Kupfer A, Preisig R (1984) Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 26:753-759 https://doi.org/10.1007/BF00541938
  108. Wedlund PJ, Aslanian WS, McAllister CB, Wilkinson GR, Branch RA (1984) Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 36:773-780 https://doi.org/10.1038/clpt.1984.256
  109. Maekawa K, Harakawa N, Sugiyama E, Tohkin M, Kim SR, Kaniwa N, Katori N, Hasegawa R, Yasuda K, Kamide K, Miyata T, Saito Y, Sawada J (2009) Substrate-dependent functional alterations of seven CYP2C9 variants found in Japanese subjects. Drug Metab Dispos 37:1895-1903. https://doi.org/10.1124/dmd.109.027003
  110. Akiyoshi T, Saito T, Murase S, Miyazaki M, Murayama N, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H (2011) Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants. Drug Metab Dispos 39:724-728. https://doi.org/10.1124/dmd.110.036780
  111. Roberts JD (1961) Nuclear magnetic resonance spectroscopy. J Chem Educ 38:581. https://doi.org/10.1021/ed038p581
  112. Krauser JA, Voehler M, Tseng LH, Schefer AB, Godejohann M, Guengerich FP (2004) Testosterone 1β-hydroxylation by human cytochrome P450 3A4. Eur J Biochem 271:3962-3969. https://doi.org/10.1111/j.1432-1033.2004.04339.x
  113. James AT, Martin AJ (1952) Gas-liquid partition chromatography; the separation and micro-estimation of volatile fatty acids from formic acid to dodecanoic acid. Biochem J 50:679-690. https://doi.org/10.1042/bj0500679
  114. Watson JT, Biemann K (1965) Direct recording of high resolution mass spectra of gas chromatographic effluents. J Mass Spectrom 37:844-851. https://doi.org/10.1002/(SICI)1096-9888(199802)33:2<109::AID-JMS634>3.0.CO;2-E
  115. Whitehouse CM, Dreyer RN, Yamashita M, Fenn JB (1985) Electrospray interface for liquid chromatographs and mass spectrometers. Anal Chem 57:675-679. https://doi.org/10.1021/ac00280a023
  116. Caprioli RM, Farmer TB, Gile J (1997) Molecular imaging of biological samples: localization of peptides and proteins using MALDI-TOF MS. Anal Chem 69:4751-4760 https://doi.org/10.1021/ac970888i
  117. Shah RR, Oates NS, Idle JR, Smith RL, Lockhart JDF (1982) Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br Med J 284:295-299 https://doi.org/10.1136/bmj.284.6312.295
  118. Oates NS, Shah RR, Idle JR, Smith RL (1981) Phenformin-induced lactic acidosis associated with impaired debrisoquine hydroxylation. Lancet 1:837-838
  119. Oates NS, Shah RR, Drury PL, Idle JR, Smith RL (1982) Captopril-induced agranulocytosis associated with an impairment of debrisoquine hydroxylation. Br J Pharmacol 14:601P
  120. Sohn JA, Kim HS, Oh J, Cho JY, Yu KS, Lee J, Shin SH, Lee JA, Choi CW, Kim EK, Kim BI, Park EA (2017) Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants. Br J Clin Pharmacol 83:1279-1286. https://doi.org/10.1111/bcp.13211
  121. Muroi Y, Saito T, Takahashi M, Sakuyama K, Niinuma Y, Ito M, Tsukada C, Ohta K, Endo Y, Oda A, Hirasawa N, Hiratsuka M (2014) Functional characterization of wild-type and 49 CYP2D6 allelic variants for N-desmethyltamoxifen 4-hydroxylation activity. Drug Metab Pharmacokinet 29:360-366. https://doi.org/10.2133/dmpk.DMPK-14-RG-014
  122. Sakuyama K, Sasaki T, Ujiie S, Obata K, Mizugaki M, Ishikawa M, Hiratsuka M (2008) Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57). Drug Metab Dispos 36:2460. https://doi.org/10.1124/dmd.108.023242
  123. Johansson I, Lundqvist E, Bertilsson L, Dahl ML, Sjoqvist F, Ingelman-Sundberg M (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 90:11825-11829 https://doi.org/10.1073/pnas.90.24.11825
  124. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ (2006) Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 368:704. https://doi.org/10.1016/S0140-6736(06)69255-6
  125. Obach RS, Cox LM, Tremaine LM (2005) Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos 33:262-270. https://doi.org/10.1124/dmd.104.002428
  126. Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E, Wilkinson GR, Branch RA (1985) Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 38:402-408 https://doi.org/10.1038/clpt.1985.194
  127. Bailey DG, Dresser G, Arnold JM (2013) Grapefruit-medication interactions: forbidden fruit or avoidable consequences? Can Med Assoc J 185:309-316. https://doi.org/10.1503/cmaj.120951
  128. Bosron WF, Li TK, Vallee BL (1979) Heterogeneity and new molecular forms of human liver alcohol dehydrogenase. Biochem Biophys Res Commun 91:1549-1555 https://doi.org/10.1016/0006-291X(79)91241-5
  129. Edenberg HJ, Bosron WF (2010) Alcohol dehydrogenases. In: Guengerich FP (ed) Biotransformation. Comprehensive toxicology (McQueen CA series ed), 4th edn. Elsevier, New York, pp 111-130
  130. Orme-Johnson WH, Ziegler DM (1965) Alcohol mixed function oxidase activity of mammalian liver micoromes. Biochem Biophys Res Commun 21:78-82 https://doi.org/10.1016/0006-291X(65)90429-8
  131. Lieber CS, DeCarli LM (1970) Hepatic microsomal ethanol oxidizing system: in vitro chracteristics and adaptive properties in vivo. J Biol Chem 245:2505-2512 https://doi.org/10.1016/S0021-9258(18)63099-6
  132. Coon MJ, Koop DR, Morgan ET (1983) Alcohol oxidation by isozyme 3a of liver microsomal cytochrome P-450. Pharmacol Biochem Behavior 18:177-180 https://doi.org/10.1016/0091-3057(83)90168-5
  133. Ryan DE, Ramanathan L, Iida S, Thomas PE, Haniu M, Shively JE, Lieber CS, Levin W (1985) Characterization of a major form of rat hepatic microsomal cytochrome P-450 induced by isoniazid. J Biol Chem 260:6385-6393 https://doi.org/10.1016/S0021-9258(18)88984-0
  134. Wrighton SA, Thomas PE, Ryan DE, Levin W (1987) Purification and characterization of ethanol-inducible human hepatic cytochrome P-450HLj. Arch Biochem Biophys 258:292-297 https://doi.org/10.1016/0003-9861(87)90347-X
  135. Kunitoh S, Imaoka S, Hiroi T, Yabusaki Y, Monna T, Funae Y (1997) Acetaldehyde as well as ethanol is metabolized by human CYP2E1. J Exp Pharmacol Ther 280:527-532
  136. Terelius Y, Norsten-Hoog C, Cronholm T, Ingelman-Sundberg M (1991) Acetaldehyde as a substrate for ethanol-inducible cytochrome P450 (CYP2E1). Biochem Biophys Res Commun 179:689-694 https://doi.org/10.1016/0006-291X(91)91427-E
  137. Bell-Parikh LC, Guengerich FP (1999) Kinetics of cytochrome P450 2E1-catalyzed oxidation of ethanol to acetic acid via acetaldehyde. J Biol Chem 274:23833-23840 https://doi.org/10.1074/jbc.274.34.23833
  138. Kono H, Bradford BU, Yin M, Sulik KK, Koop DR, Peters JM, Gonzalez FJ, McDonald T, Dikalova A, Kadiiska MB, Mason RP, Thurman RG (1999) CYP2E1 is not involved in early alcohol-induced liver injury. Am J Physiol 277:G1259-G1267
  139. Balbo S, Hashibe M, Gundy S, Brennan P, Canova C, Simonato L, Merletti F, Richiardi L, Agudo A, Castellsague X, Znaor A, Talamini R, Bencko V, Holcatova I, Wang M, Hecht SS, Boffetta P (2008) N2-Ethyldeoxyguanosine as a potential biomarker for assessing effects of alcohol consumption on DNA. Cancer Epidemiol Biomark Prev 17:3026-3032 https://doi.org/10.1158/1055-9965.EPI-08-0117
  140. Guengerich FP (2020) Cytochrome P450 2E1 and its roles in disease. Chem Biol Interact 322:109056. https://doi.org/10.1016/j.cbi.2020.109056
  141. Nelson SD (1982) Metabolic activation and drug toxicity. J Med Chem 25:753-765 https://doi.org/10.1021/jm00349a001
  142. Guengerich FP (2001) Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14:611-650 https://doi.org/10.1021/tx0002583
  143. Driscoll JP, Sadlowski CM, Shah NR, Feula A (2020) Metabolism and bioactivation: it's time to expect the unexpected. J Med Chem. https://doi.org/10.1021/acs.jmedchem.0c00026
  144. Cerny MA, Kalgutkar AS, Obach RS, Sharma R, Spracklin DK, Walker GS (2020) Effective application of metabolite profiling in drug design and discovery. J Med Chem. https://doi.org/10.1021/acs.jmedchem.9b01840
  145. Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, O'Donnell JP (2002) Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol 15:269-299 https://doi.org/10.1021/tx015574b
  146. Kalgutkar AS, Soglia JR (2005) Minimising the potential for metabolic activation in drug discovery. Expert Opin Drug Metab Toxicol 1:91-141 https://doi.org/10.1517/17425255.1.1.91
  147. Stepan AF, Walker DP, Bauman J, Price DA, Baillie TA, Kalgutkar AS, Aleo MD (2011) Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol 24:1345-1410. https://doi.org/10.1021/tx200168d
  148. Beaune P, Dansette PM, Mansuy D, Kiffel L, Finck M, Amar C, Leroux JP, Homberg JC (1987) Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. Proc Natl Acad Sci USA 84:551-555 https://doi.org/10.1073/pnas.84.2.551
  149. Dansette PM, Bertho G, Mansuy D (2005) First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives. Biochem Biophys Res Commun 338:450-455 https://doi.org/10.1016/j.bbrc.2005.08.091
  150. Lecoeur S, Bonierbale E, Challine D, Gautier JC, Valadon P, Dansette PM, Catinot R, Ballet F, Mansuy D, Beaune PH (1994) Specificity of in vitro covalent binding of tienilic acid metabolites to human liver microsomes in relationship to the type of hepatotoxicity: comparison with two directly hepatotoxic drugs. Chem Res Toxicol 7:434-442 https://doi.org/10.1021/tx00039a023
  151. Beaune P, Pessayre D, Dansette P, Mansuy D, Manns M (1994) Autoantibodies against cytochromes P450: role in human diseases. Adv Pharmacol 30:199-245 https://doi.org/10.1016/S1054-3589(08)60175-1
  152. Dansette PM, Bonierbale E, Minoletti C, Beaune PH, Pessayre D, Mansuy D (1998) Drug-induced immunotoxicity. Eur J Drug Metab Pharmacokinet 23:443-451. https://doi.org/10.1007/BF03189993
  153. Munns AJ, DeVoss JJ, Hooper WD, Dickinson RG, Gillam EMJ (1997) Bioactivation of phenytoin by human cytochrome P450: characterization of the mechanism and targets of covalent adduct formation. Chem Res Toxicol 10:1049-1058 https://doi.org/10.1021/tx9700836
  154. Bourdi M, Larrey D, Nataf J, Berunau J, Pessayre D, Iwasaki M, Guengerich FP, Beaune PH (1990) A new anti-liver endoplasmic reticulum antibody directed against human cytochrome P-450 IA2: a specific marker of dihydralazine-induced hepatitis. J Clin Invest 85:1967-1973 https://doi.org/10.1172/JCI114660
  155. Manns MP, Griffin KJ, Quattrochi LC, Sacher M, Thaler H, Tukey RH, Johnson EF (1990) Identification of cytochrome P450IA2 as a human autoantigen. Arch Biochem Biophys 280:229-232 https://doi.org/10.1016/0003-9861(90)90541-6
  156. Manns MP, Johnson EF, Griffin KJ, Tan EM, Sullivan KF (1989) Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1. J Clin Invest 83:1066-1072 https://doi.org/10.1172/JCI113949
  157. Eliasson E, Kenna JG (1996) Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis. Mol Pharmacol 50:573-582
  158. Bourdi M, Chen W, Peter RM, Martin JL, Buters JTM, Nelson SD, Pohl LR (1996) Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. Chem Res Toxicol 9:1159-1166 https://doi.org/10.1021/tx960083q
  159. Hoet P, Graf MLM, Bourdi M, Pohl LR, Chen W, Peter RM, Nelson SD, Verliinden N, Lison D (1997) Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons. Lancet 350:556-558 https://doi.org/10.1016/S0140-6736(97)03094-8
  160. Leeder JS, Riley RJ, Cook VA, Spielberg SP (1992) Human anti-cytochrome P450 antibodies in aromatic anticonvulsant-induced hypersensitivity reactions. J Exp Pharmacol Ther 263:360-367
  161. Leeder JS, Gaedigk A, Lu X, Cook VA (1996) Epitope mapping studies with human anti-cytochrome P450 3A antibodies. Mol Pharmacol 49:234-243
  162. Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z, Bharadwaj M, Miles JJ, Kjer-Nielsen L, Gras S, Williamson NA, Burrows SR, Purcell AW, Rossjohn J, McCluskey J (2012) Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486:554-558. https://doi.org/10.1038/nature11147
  163. Reinherz EL (2012) Pharmacology: a false sense of non-self. Nature 486:479-481. https://doi.org/10.1038/486479a
  164. Montane E, Arellano AL, Sanz Y, Roca J, Farre M (2018) Drug-related deaths in hospital inpatients: a retrospective cohort study. Br J Clin Pharmacol 84:542-552. https://doi.org/10.1111/bcp.13471
  165. Guengerich FP (2014) Cytochrome P450-mediated drug interactions and cardiovascular toxicity: the Seldane to Allegra transformation. In: Wang J, Urban L (eds) Predictive ADMET: integrated approaches in drug discovery and development, 1st edn. Wiley, New York, pp 523-534
  166. Kivisto KT, Neuvonen PJ, Klotz U (1994) Inhibition of terfenadine metabolism: pharmacokinetic and pharmacodynamic consequences. Clin Pharmacokinet 27:1-5 https://doi.org/10.2165/00003088-199427010-00001
  167. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR (1993) Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. J Am Med Assoc 269:1513-1518 https://doi.org/10.1001/jama.1993.03500120051025
  168. Bailey DG, Spence JD, Munoz C, Arnold JMO (1991) Interactions of citrus juices with felodipine and nifedipine. Lancet 337:251-272
  169. Guengerich FP, Brian WR, Iwasaki M, Sari MA, Baarnhielm C, Berntsson P (1991) Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4. J Med Chem 34:1838-1844 https://doi.org/10.1021/jm00110a012
  170. Paine MF, Criss AB, Watkins PB (2004) Two major grapefruit juice components differ in time to onset of intestinal CYP3A4 inhibition. J Exp Pharmacol Ther 312:1151-1160. https://doi.org/10.1124/jpet.104.076836
  171. Lin HL, Kenaan C, Hollenberg PF (2012) Identification of the residue in human CYP3A4 that is covalently modified by bergamottin and the reactive intermediate that contributes to the grapefruit juice effect. Drug Metab Dispos 40:998-1006. https://doi.org/10.1124/dmd.112.044560
  172. He K, Iyer R, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF (1998) Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice. Chem Res Toxicol 11:252-259 https://doi.org/10.1021/tx970192k
  173. Bailey DG, Arnold JMO, Munoz C, Spence JD (1993) Grapefruit juice-felodipine interaction: mechanism, predictability, and effect of naringin. Clin Pharmacol Ther 53:637-642 https://doi.org/10.1038/clpt.1993.84
  174. Bailey DG, Arnold JMO, Bend JR, Tran LT, Spence JD (1995) Grapefruit juice-felodipine interaction: reproducibility and characterization with the extended release drug formulation. Br J Clin Pharmacol 40:135-140
  175. Lilja JJ, Kivisto KT, Neuvonen PJ (1999) Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 66:118-127 https://doi.org/10.1053/cp.1999.v66.100453001
  176. Reimers D, Jezek A (1971) Rifampicin und andere Antituberkulotika bei gleichzeitiger oraler Kontrzeption. Przx Pneumolonol 25:255-262
  177. Nocke-Finck L, Brewer H, Reimers D (1973) Wirkung von Rifampicin auf den Menstruationszyklus und die Ostrogenausscheidung bei Einnahme oraler Kontrazeptiva. Dtsch Med Wochenschr 98:1521-1523 https://doi.org/10.1055/s-0028-1107071
  178. Guengerich FP (1988) Oxidation of 17α-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol 33:500-508
  179. Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL (2005) Interaction of St. John's wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 71:402-408 https://doi.org/10.1016/j.contraception.2004.11.004
  180. Moore LG, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Wilson TM, Collins JL, Kliewer SA (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 97:7500-7502 https://doi.org/10.1073/pnas.130155097
  181. Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I, Brockmoller J (2004) Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 9:442-473. https://doi.org/10.1038/sj.mp.4001494
  182. Greenblatt DJ, Venkatakrishnan K, Harmatz JS, Parent SJ, von Moltke LL (2010) Sources of variability in ketoconazole inhibition of human cytochrome P450 3A in vitro. Xenobiotica 40:713-720. https://doi.org/10.3109/00498254.2010.506224
  183. Zimmerlin A, Trunzer M, Faller B (2011) CYP3A time-dependent inhibition risk assessment validated with 400 reference drugs. Drug Metab Dispos 39:1039-1046. https://doi.org/10.1124/dmd.110.037911
  184. Eng H, Tseng E, Lin J, Goosen TC, Cerny MA, Obach RS (2019) Delineation of in vitro cut-off values for CYP3A4/5 time-dependent inhibiton useful in early drug design-a side-by-side comarison in human liver microsomes and hepatocytes. In: Abstracts, 12th International Int Soc Study Xenobiotics meeting, Portland, OR, July
  185. Guengerich FP (2015) Human cytochrome P450 enzymes. In: Ortiz de Montellano PR (ed) Cytochrome P450: structure, mechanism, and biochemistry, vol 2, 4th edn. Springer, New York, pp 523-785
  186. Guengerich FP (2020) Cytochrome P450 catalysis in natural product biosynthesis. In: Bollinger M, Booker S, Bandarian V (eds) Comprehensive natural products, III: chemistry and biology, radicals and metalloenzymology, 5th edn. Elsevier, New York
  187. Rendic S, Guengerich FP (2018) Human cytochrome P450 enzymes 5-51 as targets of drugs, natural, and environmental compounds: mechanisms, induction, and inhibition-toxic effects and benefits. Drug Metab Rev 50:256-342 https://doi.org/10.1080/03602532.2018.1483401
  188. Zhang D, Flint O, Wang L, Gupta A, Westhouse RA, Zhao W, Raghavan N, Caceres-Cortes J, Marathe P, Shen G, Zhang Y, Allentoff A, Josephs J, Gan J, Borzilleri R, Humphreys WG (2012) Cytochrome P450 11A1 bioactivation of a kinase inhibitor in rats: use of radioprofiling, modulation of metabolism, and adrenocortical cell lines to evaluate adrenal toxicity. Chem Res Toxicol 25:556-571. https://doi.org/10.1021/tx200524d
  189. Mast N, Norcross R, Andersson U, Shou M, Nakayama K, Bjorkhem I, Pikuleva IA (2003) Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry 42:14284-14292 https://doi.org/10.1021/bi035512f
  190. Mast N, Anderson KW, Johnson KM, Phan TTN, Guengerich FP, Pikuleva IA (2017) In vitro cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds. J Biol Chem 292:12934-12946. https://doi.org/10.1074/jbc.M117.794909
  191. Jewell SA, Bellomo G, Thor H, Orrenius S, Smith MT (1982) Bleb formation in hepatocytes during drug metabolism is caused by disturbances in thiol and calcium ion homeostasis. Science 217:1257-1259 https://doi.org/10.1126/science.7112127
  192. Farber JL (1990) The role of calcium in lethal cell injury. Chem Res Toxicol 3:503-508 https://doi.org/10.1021/tx00018a003
  193. Lehman-McKeeman LD (2019) Mechanisms of toxicity. In: Klaassen CD (ed) Casarett and Doull's toxicology: the basic science of poisons, 3rd edn. pp 65-125
  194. Thompson RA, Isin EM, Li Y, Weidolf L, Page K, Wilson I, Swallow S, Middleton B, Stahl S, Foster AJ, Dolgos H, Weaver R, Kenna JG (2012) In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem Res Toxicol 25:1616-1632. https://doi.org/10.1021/tx300091x
  195. Thompson RA, Isin EM, Ogese MO, Mettetal JT, Williams DP (2016) Reactive metabolites: current and emerging risk and hazard assessments. Chem Res Toxicol 29:505-533. https://doi.org/10.1021/acs.chemrestox.5b00410
  196. Edwards SW, Tan Y-M, Villeneuve DL, Meek ME, McQueen CA (2016) Adverse outcome pathways-organizing toxicological information to improve decision making. J Exp Pharmacol Ther 356:170-181. https://doi.org/10.1124/jpet.115.228239
  197. Weaver RJ, Blomme EA, Chadwick AE, Copple IM, Gerets HHJ, Goldring CE, Guillouzo A, Hewitt PG, Ingelman-Sundberg M, Jensen KG, Juhila S, Klingmuller U, Labbe G, Liguori MJ, Lovatt CA, Morgan P, Naisbitt DJ, Pieters RHH, Snoeys J, van de Water B, Williams DP, Park BK (2020) Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models. Nat Rev Drug Discov 19:131-148. https://doi.org/10.1038/s41573-019-0048-x
  198. Rana P, Aleo MD, Gosink M, Will Y (2019) Evaluation of in vitro mitochondrial toxicity assays and physicochemical properties for prediction of organ toxicity using 228 pharmaceutical drugs. Chem Res Toxicol 32:156-167. https://doi.org/10.1021/acs.chemrestox.8b00246
  199. Aleo MD, Shah F, Allen S, Barton HA, Costales C, Lazzaro S, Leung L, Nilson A, Obach RS, Rodrigues AD, Will Y (2020) Moving beyond binary predictions of human drug-induced liver injury (DILI) toward contrasting relative risk potential. Chem Res Toxicol 33:223-238. https://doi.org/10.1021/acs.chemrestox.9b00262
  200. Weaver RJ, Valentin JP (2019) Today's challenges to de-risk and predict drug safety in human "Mind-the-Gap". Toxicol Sci 167:307-321. https://doi.org/10.1093/toxsci/kfy270
  201. Hsieh JH, Smith-Roe SL, Huang R, Sedykh A, Shockley KR, Auerbach SS, Merrick BA, Xia M, Tice RR, Witt KL (2019) Identifying compounds with genotoxicity potential using Tox21 high-throughput screening assays. Chem Res Toxicol 32:1384-1401. https://doi.org/10.1021/acs.chemrestox.9b00053
  202. Fink-Gremmels J (2008) Implications of hepatic cytochrome P450-related biotransformation processes in veterinary sciences. Eur J Pharmacol 585:502-509. https://doi.org/10.1016/j.ejphar.2008.03.013
  203. Aidasani D, Zaya MJ, Malpas PB, Locuson CW (2008) In vitro drug-drug interaction screens for canine veterinary medicines: evaluation of cytochrome P450 reversible inhibition. Drug Metab Dispos 36:1512-1518 https://doi.org/10.1124/dmd.108.021196
  204. Knych HK, Baden RW, Gretler SR, McKemie DS (2019) Characterization of the in vitro CYP450 mediated metabolism of the polymorphic CYP2D6 probe drug codeine in horses. Biochem Pharmacol 168:184-192. https://doi.org/10.1016/j.bcp.2019.07.005
  205. Shin YG, Le H, Khojasteh C, Hop CE (2011) Comparison of metabolic soft spot predictions of CYP3A4, CYP2C9 and CYP2D6 substrates using MetaSite and StarDrop. Comb Chem High Throughput Screen 14:811-823 https://doi.org/10.2174/138620711796957170
  206. Trunzer M, Faller B, Zimmerlin A (2009) Metabolic soft spot identification and compound optimization in early discovery phases using MetaSite and LC-MS/MS validation. J Med Chem 52:329-335. https://doi.org/10.1021/jm8008663
  207. Cruciani G, Carosati E, De Boeck B, Ethirajulu K, Mackie C, Howe T, Vianello R (2005) MetaSite: understanding metabolism in human cytochromes from the perspective of the chemist. J Med Chem 48:6970-6979 https://doi.org/10.1021/jm050529c
  208. Cunningham AR, Cunningham SL, Rosenkranz HS (2004) Structure-activity approach to the identification of environmental estrogens: the MCASE approach. SAR QSAR Environ Res 15:55-67. https://doi.org/10.1080/1062936032000169679
  209. Mayer J, Cheeseman MA, Twaroski ML (2008) Structure-activity relationship analysis tools: validation and applicability in predicting carcinogens. Regul Toxicol Pharmacol 50:50-58. https://doi.org/10.1016/j.yrtph.2007.09.005
  210. Dearden JC (2003) In silico prediction of drug toxicity. J Comput Aided Mol Des 17:119-127 https://doi.org/10.1023/A:1025361621494

Cited by

  1. Role of Genetic Variation in Cytochromes P450 in Breast Cancer Prognosis and Therapy Response vol.22, pp.6, 2021, https://doi.org/10.3390/ijms22062826
  2. In Silico Analysis of P450s and Their Role in Secondary Metabolism in the Bacterial Class Gammaproteobacteria vol.26, pp.6, 2021, https://doi.org/10.3390/molecules26061538
  3. Current Strategies in Assessment of Nanotoxicity: Alternatives to In Vivo Animal Testing vol.22, pp.8, 2021, https://doi.org/10.3390/ijms22084216
  4. Is There an Increased Risk of Hepatotoxicity with Metamizole? A Comparative Cohort Study in Incident Users vol.44, pp.9, 2021, https://doi.org/10.1007/s40264-021-01087-7
  5. Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design vol.64, pp.19, 2021, https://doi.org/10.1021/acs.jmedchem.1c01215
  6. Genetic variations and epigenetic modulations in CYP genes: Implications in NSAID-treatment of arthritis patients vol.64, pp.3, 2021, https://doi.org/10.1007/s13237-021-00373-0
  7. Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms vol.10, pp.12, 2021, https://doi.org/10.3390/cells10123472