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Annual Review of Pharmacology and Toxicology

Volume 62, 2022

Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development

Abstract

Most clinically used drugs are metabolized in the body via oxidation, reduction, or hydrolysis reactions, which are considered phase I reactions. Cytochrome P450 (P450) enzymes, which primarily catalyze oxidation reactions, contribute to the metabolism of over 50% of clinically used drugs. In the last few decades, the function and regulation of P450s have been extensively studied, whereas the characterization of non-P450 phase I enzymes is still incomplete. Recent studies suggest that approximately 30% of drug metabolism is carried out by non-P450 enzymes. This review summarizes current knowledge of non-P450 phase I enzymes, focusing on their roles in controlling drug efficacy and adverse reactions as an important aspect of drug development.

Keyword(s): drug development, hydrolysis, non-P450 enzymes, oxidation, phase I metabolism, reduction
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/content/journals/10.1146/annurev-pharmtox-052220-105907
2022-01-06
2024-06-27
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Literature Cited

  1. 1. 
    Cerny MA. 2016. Prevalence of non-cytochrome P450-mediated metabolism in Food and Drug Administration-approved oral and intravenous drugs: 2006–2015. Drug Metab. Dispos. 44:1246–52
     [Google Scholar]
  2. 2. 
    Zhang J, Cashman JR. 2006. Quantitative analysis of FMO gene mRNA levels in human tissues. Drug Metab. Dispos. 34:19–26
     [Google Scholar]
  3. 3. 
    Dolphin CT, Beckett DJ, Janmohamed A, Cullingford TE, Smith RL et al. 1998. The flavin-containing monooxygenase 2 gene (FMO2) of humans, but not of other primates, encodes a truncated, nonfunctional protein. J. Biol. Chem. 273:30599–607
     [Google Scholar]
  4. 4. 
    Whetstine JR, Yueh MF, McCarver DG, Williams DE, Park CS et al. 2000. Ethnic differences in human flavin-containing monooxygenase 2 (FMO2) polymorphisms: detection of expressed protein in African-Americans. Toxicol. Appl. Pharmacol. 168:216–24
     [Google Scholar]
  5. 5. 
    Krueger SK, Williams DE, Yueh MF, Martin SR, Hines RN et al. 2002. Genetic polymorphisms of flavin-containing monooxygenase (FMO). Drug Metab. Rev. 34:523–32
     [Google Scholar]
  6. 6. 
    Henderson MC, Siddens LK, Morré JT, Krueger SK, Williams DE. 2008. Metabolism of the anti-tuberculosis drug ethionamide by mouse and human FMO1, FMO2 and FMO3 and mouse and human lung microsomes. Toxicol. Appl. Pharmacol. 233:420–27
     [Google Scholar]
  7. 7. 
    Phillips IR, Shephard EA. 2020. Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease. Xenobiotica 50:19–33
     [Google Scholar]
  8. 8. 
    Shephard EA, Treacy EP, Phillips IR. 2015. Clinical utility gene card for: trimethylaminuria—update 2014. Eur. J. Hum. Genet. 23:1269
     [Google Scholar]
  9. 9. 
    Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR. 1997. Missense mutation in flavon-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat. Genet. 17:491–94
     [Google Scholar]
  10. 10. 
    Cashman JR, Park SB, Yang ZC, Washington CB, Gomez DY et al. 1993. Chemical, enzymatic, and human enantioselective S-oxygenation of cimetidine. Drug Metab. Dispos. 21:587–97
     [Google Scholar]
  11. 11. 
    Chung WG, Park CS, Roh HK, Lee WK, Cha YN. 2000. Oxidation of ranitidine by isozymes of flavin-containing monooxygenase and cytochrome P450. Jpn. J. Pharmacol. 84:213–20
     [Google Scholar]
  12. 12. 
    Etienne F, Resnick L, Sagher D, Brot N, Weissbach H. 2003. Reduction of sulindac to its active metabolite, sulindac sulfide: assay and role of the methionine sulfoxide reductase system. Biochem. Biophys. Res. Commun. 312:1005–10
     [Google Scholar]
  13. 13. 
    Hamman MA, Haehner-Daniels BD, Wrighton SA, Rettie AE, Hall SD. 2000. Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases: comparison of human liver and kidney microsomes and mammalian enzymes. Biochem. Pharmacol. 60:7–17
     [Google Scholar]
  14. 14. 
    Fiorentini F, Romero E, Fraajie MW, Faber K, Hall M et al. 2017. Baeyer-Villiger monooxygenase FMO5 as entry point in drug metabolism. ACS Chem. Biol. 12:2379–87
     [Google Scholar]
  15. 15. 
    Matsumoto K, Hasegawa T, Ohara K, Takei C, Kamei T et al. 2020. A metabolic pathway for the prodrug nabumetone to the pharmacologically active metabolite, 6-methoxy-2-naphtyhylacetic acid (6-MNA) by non-cytochrome P450 enzymes. Xenobiotica 50:783–92
     [Google Scholar]
  16. 16. 
    Turpeinen M, Hofmann U, Klein K, Mürdter T, Schwab M et al. 2009. A predominate role of CYP1A2 for the metabolism of nabumetone to the active metabolite, 6-methoxy-2-naphthylacetic acid, in human liver microsomes. Drug Metab. Dispos. 37:1017–24
     [Google Scholar]
  17. 17. 
    Varfaj F, Zulkifli SNA, Park HG, Challinor VL, De Voss JJ et al. 2014. Carbon-carbon bond cleavage in activation of the prodrug nabumetone. Drug Metab. Dispos. 42:828–38
     [Google Scholar]
  18. 18. 
    Edenberg HJ. 2007. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res. Health 30:5–13
     [Google Scholar]
  19. 19. 
    Edenberg HJ, McClintick JN. 2018. Alcohol dehydrogenases, aldehyde dehydrogenases, and alcohol use disorders: a critical review. Alcohol Clin. Exp. Res. 42:2281–97
     [Google Scholar]
  20. 20. 
    Walsh JS, Reese MJ, Thurmond LM. 2002. The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes. Chem. Biol. Interact. 142:135–54
     [Google Scholar]
  21. 21. 
    Sandberg M, Yasar U, Strömberg P, Höög JO, Eliasson E. 2002. Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase. Br. J. Clin. Pharmacol. 54:423–29
     [Google Scholar]
  22. 22. 
    Nishiya Y, Nakai D, Urasaki Y, Takakusa H, Ohsuki S et al. 2016. Stereoselective hydroxylation by CYP2C19 and oxidation by ADH4 in the in vitro metabolism of tivantinib. Xenobiotica 46:967–76
     [Google Scholar]
  23. 23. 
    Chen G, Højer AM, Areberg J, Nomikos G. 2017. Vortioxetine: clinical pharmacokinetics and drug interactions. Clin. Pharmacokinet. 57:673–86
     [Google Scholar]
  24. 24. 
    Vasiliou V, Nebert DW. 2005. Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum. Genom. 2:138–43
     [Google Scholar]
  25. 25. 
    Zhou L, Sheng D, Wang D, Ma W, Deng Q et al. 2018. Identification of cancer-type specific expression patterns for active aldehyde dehydrogenase (ALDH) isoforms in ALDEFLUOR assay. Cell Biol. Toxicol. 35:161–177
     [Google Scholar]
  26. 26. 
    Wang X, He B, Shi J, Li Q, Zhu HJ. 2020. Comparative proteomics analysis of human liver microsomes and S9 fractions. Drug Metab. Dispos. 48:31–40
     [Google Scholar]
  27. 27. 
    Crabb DW, Edenberg HJ, Bosron WF, Li TK. 1989. Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. J. Clin. Investig. 83:314–16
     [Google Scholar]
  28. 28. 
    Laskar AA, Younus H. 2019. Aldehyde toxicity and metabolism: the role of aldehyde dehydrogenases in detoxification, drug resistance and carcinogenesis. Drug Metab. Rev. 51:42–64
     [Google Scholar]
  29. 29. 
    Andersson BS, Mroue M, Britten RA, Murray D. 1994. The role of DNA damage in the resistance of human chronic myeloid leukemia cells to cyclophosphamide analogues. Cancer Res 54:5394–400
     [Google Scholar]
  30. 30. 
    Sládek NE. 2002. Leukemic cell insensitivity to cyclophosphamide and other oxazaphosphorines mediated by aldehyde dehydrogenase(s). Cancer Treat Res 112:161–75
     [Google Scholar]
  31. 31. 
    Elion GB. 1989. The purine path to chemotherapy. Science 244:41–47
     [Google Scholar]
  32. 32. 
    Ansari A, Elliott T, Baburajan B, Mayhead P, O'Donohue J et al. 2008. Long-term outcome of using allopurinol co-therapy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease. Aliment. Pharmacol. Ther. 28:734–41
     [Google Scholar]
  33. 33. 
    Matsuo K, Sasaki E, Higuchi S, Takai S, Tsuneyama K et al. 2014. Involvement of oxidative stress and immune- and inflammation-related factors in azathioprine-induced liver injury. Toxicol. Lett. 224:215–24
     [Google Scholar]
  34. 34. 
    Barr JT, Choughule KV, Nepal S, Wong T, Chaudhry AS et al. 2014. Why do most human liver cytosol preparations lack xanthine oxidase activity?. Drug Metab. Dispos. 42:695–99
     [Google Scholar]
  35. 35. 
    Kurosaki M, Bolis M, Fratelli M, Barzago MM, Pattini L et al. 2013. Structure and evolution of vertebrate aldehyde oxidases: from gene duplication to gene suppression. Cell Mol. Life Sci. 70:1807–30
     [Google Scholar]
  36. 36. 
    Sanoh S, Tayama Y, Sugihara K, Kitamura S, Ohta S. 2015. Significance of aldehyde oxidase during drug development: effects on drug metabolism, pharmacokinetics, toxicity, and efficacy. Drug Metab. Pharmacokinet. 30:52–63
     [Google Scholar]
  37. 37. 
    Beedham C. 1985. Molybdenum hydroxylases as drug-metabolizing enzymes. Drug Metab. Rev. 16:119–56
     [Google Scholar]
  38. 38. 
    Sodhi JK, Wong S, Kirkpatrick DS, Liu L, Khojasteh C et al. 2015. A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834. Drug Metab. Dispos. 43:908–15
     [Google Scholar]
  39. 39. 
    Peppercom MA, Goldman P. 1972. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J. Pharmacol. Exp. Ther. 181:555–62
     [Google Scholar]
  40. 40. 
    Masunaga S, Ono K, Hori H, Suzuki M, Kinashi Y et al. 2000. Change in oxygenation status in intratumour total and quiescent cells following gamma-ray irradiation, tirapazamine administration, cisplatin injection and bleomycin treatment. Br. J. Radiol. 73:978–86
     [Google Scholar]
  41. 41. 
    Zurth C, Koskinen M, Fricke R, Prien O, Korjamo T et al. 2019. Drug-drug interaction potential of darolutamide: in vitro and clinical studies. Eur. J. Drug Metab. Pharmacokinet. 44:747–59
     [Google Scholar]
  42. 42. 
    Weng J, Cao Y, Moss N, Zhou M. 2006. Modulation of voltage-dependent Shaker family potassium channels by an aldo-keto reductase. J. Biol. Chem. 281:15194–200
     [Google Scholar]
  43. 43. 
    Tipparaju SM, Barski OA, Srivastava S, Bhatnagar A. 2008. Catalytic mechanism and substrate specificity of the β-subunit of the voltage-gated potassium channel. Biochemistry 47:8840–54
     [Google Scholar]
  44. 44. 
    Amai K, Fukami T, Ichida H, Watanabe A, Nakano M et al. 2020. Quantitative analysis of mRNA expression levels of aldo-keto reductase and short-chain dehydrogenase/reductase isoforms in human livers. Drug Metab. Pharmacokinet. 35:539–47
     [Google Scholar]
  45. 45. 
    Ohara H, Miyabe Y, Deyashiki Y, Matsuura K, Hara A. 1995. Reduction of drug ketones by dihydrodiol dehydrogenases, carbonyl reductase and aldehyde reductase of human liver. Biochem. Pharmacol. 50:221–27
     [Google Scholar]
  46. 46. 
    Kassner N, Huse K, Martin HJ, Gödtel-Armbrust U, Metzger A et al. 2008. Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug Metab. Dispos. 36:2113–20
     [Google Scholar]
  47. 47. 
    Fukumoto S, Yamauchi N, Moriguchi H, Hippo Y, Watanabe A et al. 2005. Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smoker's non-small lung carcinoma. Clin. Cancer Res. 11:1776–85
     [Google Scholar]
  48. 48. 
    Liu Z, Yan R, Al-Salman A, Shen Y, Bu Y et al. 2012. Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signaling in hepatocellular carcinoma cells. Biochem. J. 442:273–82
     [Google Scholar]
  49. 49. 
    Penning TM. 2005. AKR1B10: a new diagnostic marker of non-small cell lung carcinoma in smokers. Clin. Cancer Res. 11:1687–90
     [Google Scholar]
  50. 50. 
    Gallego O, Ruiz FX, Ardévol A, Domínguez M, Alvarez R et al. 2007. Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10. PNAS 104:20764–69
     [Google Scholar]
  51. 51. 
    Martin HJ, Breyer-Praff U, Wsol V, Venz S, Block S et al. 2006. Purification and characterization of AKR1B10 from human liver: role in carbonyl reduction of xenobiotics. Drug Metab. Dispos. 34:464–70
     [Google Scholar]
  52. 52. 
    Ahmed MME, Wang TW, Luo Y, Ye S, Wu Q et al. 2011. Aldo-keto reductase-7A protects liver cells and tissues from acetaminophen-induced oxidative stress and hepatotoxicity. Hepatology 54:1322–32
     [Google Scholar]
  53. 53. 
    Judah DJ, Hayes JD, Yang JC, Lian LY, Roberts GC et al. 1993. A novel aldehyde reductase with activity towards a metabolite of aflatoxin B1 is expressed in rat liver during carcinogenesis and following the administration of an anti-oxidant. Biochem. J. 292:13–18
     [Google Scholar]
  54. 54. 
    Ellis EM, Judah DJ, Neal GE, Hayes JD 1993. An ethoxyquin-inducible aldehyde reductase from rat liver that metabolizes aflatoxin B1 defines a subfamily of aldo-keto reductases. PNAS 90:10350–54
     [Google Scholar]
  55. 55. 
    Persson B 2013. Classification and nomenclature of the superfamily of short-chain dehydrogenases/reductases (SDRs). Chem. Biol. Interact. 202:111–15
     [Google Scholar]
  56. 56. 
    Bray JE, Marsden BD, Oppermann U. 2009. The human short-chain dehydrogenase/reductase (SDR) superfamily: a bioinformatics summary. Chem. Biol. Interact. 178:99–109
     [Google Scholar]
  57. 57. 
    Shin JG, Kane K, Flockhart DA. 2001. Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol. Br. J. Clin. Pharmacol. 51:45–52
     [Google Scholar]
  58. 58. 
    Meyer A, Vuorinen A, Zielinska AE, Strajhar P, Lavery GG et al. 2013. Formation of threohydrobupropion from bupropion is dependent on 11β-hydroxysteroid dehydrogenase 1. Drug Metab. Dispos. 41:1671–78
     [Google Scholar]
  59. 59. 
    Hult M, Nobel CSI, Abrahmsen L, Nicoll-Griffith DA, Jörnvall H et al. 2001. Novel enzymological profiles of human 11β-hydroxysteroid dehydrogenase type 1. Chem. Biol. Interact.130–2805–14
     [Google Scholar]
  60. 60. 
    Haddock RE, Jeffery DJ, Lloyd JA, Thawley AR. 1984. Metabolism of nabumetone (BRL 14777) by various species including man. Xenobiotica 14:327–37
     [Google Scholar]
  61. 61. 
    Vasiliou V, Ross D, Nebert DW. 2006. Update of the NAD(P)H:quinone oxidoreductase (NQO) gene family. Hum. Genom. 2:329–35
     [Google Scholar]
  62. 62. 
    Wu K, Knox R, Sun XZ, Joseph P, Jaiswal AK et al. 1997. Catalytic properties of NAD(P)H:quinone oxidoreductase-2 (NQO2), a dihydronicotiamide riboside dependent oxidoreductase. Arch. Biochem. Biophys. 347:221–28
     [Google Scholar]
  63. 63. 
    Siegel D, Beall H, Senekowitsch C, Kasai M, Arai H et al. 1992. Bioreductive activation of mitomycin C by DT-diaphorase. Biochemistry 31:7879–85
     [Google Scholar]
  64. 64. 
    Beall HD, Liu Y, Siegel D, Bolton EM, Gibson NW et al. 1996. Role of NAD(P)H:quinone oxidoreductase (DT-diaphorase) in cytotoxicity and induction of DNA damage by streptonigrin. Biochem. Pharmacol. 51:645–52
     [Google Scholar]
  65. 65. 
    Gong X, Gutala R, Jaiswal AK. 2008. Quinone oxidoreductases and vitamin K metabolism. Vitam. Horm. 78:85–101
     [Google Scholar]
  66. 66. 
    Janda E, Nepveu F, Calamini B, Ferry G, Boutin JA. 2020. Molecular pharmacology of NRH:quinone oxidoreductase 2: a detoxifying enzyme acting as an undercover toxifying enzyme. Mol. Pharmacol. 98:620–33
     [Google Scholar]
  67. 67. 
    Moffit JS, Aleksunes LM, Kardas MJ, Slitt AL, Klaassen CD et al. 2007. Role of NAD(P)H:quinone oxidoreductase 1 in clofibrate-mediated hepatoprotection from acetaminophen. Toxicology 230:197–206
     [Google Scholar]
  68. 68. 
    Vredenburg G, Elias NS, Venkataraman H, Hendriks DFG, Vermeulen NPE et al. 2014. Human NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated inactivation of reactive quinoneimine metabolites of diclofenac and mefenamic acid. Chem. Res. Toxicol. 27:576–86
     [Google Scholar]
  69. 69. 
    Hwang JH, Kim YH, Noh JR, Gang GT, Kim KS et al. 2015. The protective role of NAD(P)H:quinone oxidoreductase 1 on acetaminophen-induced liver injury is associated with prevention of adenosine triphosphate depletion and improvement of mitochondrial dysfunction. Arch. Toxicol. 89:2159–66
     [Google Scholar]
  70. 70. 
    Siegel D, Ross D. 2000. Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radic. . Biol. Med. 29:246–53
     [Google Scholar]
  71. 71. 
    Nishimura M, Naito S. 2006. Tissue-specific mRNA expression profiles of human phase I metabolizing enzymes except for cytochrome P450 and phase II metabolizing enzymes. Drug Metab. Pharmacokinet. 21:357–74
     [Google Scholar]
  72. 72. 
    Cresteil T, Jaiswal AK. 1991. High levels of expression of the NAD(P)H:quinone oxidoreductase (NQO1) gene in tumor cells compared to normal cells of the same origin. Biochem. Pharmacol. 42:1021–27
     [Google Scholar]
  73. 73. 
    Coles B, Wilson I, Wardman P, Hinson JA, Nelson SD et al. 1988. The spontaneous and enzymatic reaction of N-acetyl-p-benzoquinonimine with glutathione: a stopped-flow kinetic study. Arch. Biochem. Biophys. 264:253–60
     [Google Scholar]
  74. 74. 
    Watanabe N, Dickson A, Liu R, Forman J. 2004. Quinones and glutathione metabolism. Method Enzymol 378:319–340
     [Google Scholar]
  75. 75. 
    Stepan AF, Walker DP, Bauman J, Price DA, Baillie TA et al. 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. 24:1345–410
     [Google Scholar]
  76. 76. 
    Ogiso T, Fukami T, Zhongzhe C, Konishi K, Nakano M et al. 2021. Human superoxide dismutase 1 attenuates quinoneimine metabolite formation from mefenamic acid. Toxicology 448:152648
     [Google Scholar]
  77. 77. 
    Aleksunes LM, Goedken M, Manautou JE et al. 2006. Up-regulation of NAD(P)H quinone oxidoreductase 1 during human liver injury. World J. Gastroenterol. 12:1937–40
     [Google Scholar]
  78. 78. 
    Konishi K, Fukami T, Gotoh S, Nakajima M. 2017. Identification of enzymes responsible for nitrazepam metabolism and toxicity in human. Biochem. Pharmacol. 140:150–60
     [Google Scholar]
  79. 79. 
    Amano T, Fukami T, Ogiso T, Hirose D, Jones JP et al. 2018. Identification of enzymes responsible for dantrolene metabolism in the human liver: a clue to uncover the cause of liver injury. Biochem. Pharmacol. 151:69–78
     [Google Scholar]
  80. 80. 
    Ogiso T, Fukami T, Mishiro K, Konishi K, Jones JP et al. 2018. Substrate selectivity of human aldehyde oxidase 1 in reduction of nitroaromatic drugs. Arch. Biochem. Biophys. 659:85–92
     [Google Scholar]
  81. 81. 
    Tatsumi K, Kitamura S, Yamada H. 1982. Involvement of liver aldehyde oxidase in sulfoxide reduction. Chem. Pharm. Bull. 30:4585–88
     [Google Scholar]
  82. 82. 
    Kitamura S, Nakatani K, Ohashi K, Sugihara K, Hosokawa R et al. 2001. Extremely high drug-reductase activity based on aldehyde oxidase in monkey liver. Biol. Pharm. Bull. 24:856–59
     [Google Scholar]
  83. 83. 
    Holmes RS, Wright MW, Laulederkind SJ, Cox LA, Hosokawa M et al. 2011. Recommended nomenclature for five mammalian carboxylesterase gene families: human, mouse, and rat genes and proteins. Mamm. Genome 21:427–41
     [Google Scholar]
  84. 84. 
    Xu G, Zhang W, Ma MK, McLeod HL. 2002. Human carboxylesterase 2 is commonly expressed in tumor tissue and is correlated with activation of irinotecan. Clin. Cancer Res. 8:2605–11
     [Google Scholar]
  85. 85. 
    Tabata T, Katoh M, Tokudome S, Nakajima M, Yokoi T. 2004. Identification of the cytosolic carboxylesterase catalyzing the 5′-deoxy-5-fluorocytidine formation from capecitabine in human liver. Drug Metab. Dispos. 32:1103–10
     [Google Scholar]
  86. 86. 
    Qian Y, Markowitz JS. 2020. Natural products as modulators of CES1 activity. Drug Metab. Dispos. 48:993–1007
     [Google Scholar]
  87. 87. 
    Watanabe A, Fukami T, Nakajima M, Takamiya M, Aoki Y et al. 2009. Human arylacetamide deacetylase is a principal enzyme in flutamide hydrolysis. Drug Metab. Dispos. 37:1513–20
     [Google Scholar]
  88. 88. 
    Fukami T, Takahashi S, Nakagawa S, Maruichi T, Nakajima M et al. 2010. In vitro evaluation of inhibitory effects of antidiabetic and antihyperlipidemic drugs on human carboxylesterase activities. Drug Metab. Dispos. 38:2173–78
     [Google Scholar]
  89. 89. 
    Shi D, Yang J, Yang D, LeCluyse EL, Black C et al. 2006. Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel. J. Pharmacol. Exp. Ther. 319:1477–84
     [Google Scholar]
  90. 90. 
    Tang M, Mukundan M, Yang J, Charpentier N, LeCluyse EL et al. 2006. Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol. J. Pharmacol. Exp. Ther. 319:1467–76
     [Google Scholar]
  91. 91. 
    Sun Z, Murry DJ, Sanghani SP, Davis WI, Kedishvili NY et al. 2004. Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J. Pharmacol. Exp. Ther. 310:469–76
     [Google Scholar]
  92. 92. 
    Humerickhouse R, Lohrbach L, Li L, Borson WF, Dolan ME. 2000. Characterization of irinotecan hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2. Cancer Res 60:1189–92
     [Google Scholar]
  93. 93. 
    Tang M, Mukundan M, Yang J, Charpentier N, LeCluyse EL et al. 2006. Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol. J. Pharmacol. Exp. Ther. 319:1467–76
     [Google Scholar]
  94. 94. 
    Fukami T, Kariya M, Kurokawa T, Iida A, Nakajima M. 2015. Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterase. Eur. J. Pharm. Sci. 78:47–53
     [Google Scholar]
  95. 95. 
    Kim D, Guengerich FP. 2005. Cytochrome P450 activation of arylamines and heterocyclic amines. Annu. Rev. Pharmacol. Toxicol. 45:27–49
     [Google Scholar]
  96. 96. 
    Higuchi R, Fukami T, Nakajima M, Yokoi T. 2013. Prilocaine- and lidocaine-induced methemoglobinemia is caused by human carboxylesterase-, CYP2E1-, and CYP3A4-mediated metabolic activation. Drug Metab. Dispos. 41:1220–30
     [Google Scholar]
  97. 97. 
    Kobayashi Y, Fukami T, Shimizu M, Nakajima M, Yokoi T. 2012. Contributions of arylacetamide deacetylase and carboxylesterase 2 to flutamide hydrolysis in human liver. Drug Metab. Dispos. 40:1080–84
     [Google Scholar]
  98. 98. 
    Ohbuchi M, Miyata M, Nagai D, Shimada M, Yoshinari K et al. 2009. Role of enzymatic N-hydroxylation and reduction in flutamide metabolite-induced liver toxicity. Drug Metab. Dispos. 37:97–105
     [Google Scholar]
  99. 99. 
    Muta K, Fukami T, Nakajima M. 2015. A proposed mechanism for the adverse effects of acebutolol: CES2 and CYP2C19-mediated metabolism and antinuclear antibody production. Biochem. Pharmacol. 98:659–70
     [Google Scholar]
  100. 100. 
    Konishi K, Fukami T, Ogiso T, Nakajima M. 2018. In vitro approach to elucidate the relevance of carboxylesterase 2 and N-acetyltransferase 2 to flupirtine-induced liver injury. Biochem. Pharmacol. 155:242–51
     [Google Scholar]
  101. 101. 
    Watanabe A, Fukami T, Takahashi S, Kobayashi Y, Nakagawa N et al. 2010. Arylacetamide deacetylase is a determinant enzyme for the difference in hydrolase activities of phenacetin and acetaminophen. Drug Metab. Dispos. 38:1532–37
     [Google Scholar]
  102. 102. 
    Nakajima A, Fukami T, Kobayashi Y, Watanabe A, Nakajima M et al. 2011. Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine. Biochem. Pharmacol. 82:1747–56
     [Google Scholar]
  103. 103. 
    Fukami T, Iida A, Konishi K, Nakajima M. 2016. Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity. Biochem. Pharmacol. 116:153–61
     [Google Scholar]
  104. 104. 
    Hirosawa K, Fukami T, Tashiro K, Sakai Y, Kisui F et al. 2021. Role of human arylacetamide deacetylase (AADAC) on hydrolysis of eslicarbazepine acetate and effects of AADAC genetic polymorphisms on hydrolase activity. Drug Metab. Dispos. 49:4322–29
     [Google Scholar]
  105. 104a. 
    Sakai Y, Fukami T, Nagaoka M, Hirosawa K, Ichida Het al 2021. Arylacetamide deacetylase as a determinant of the hydrolysis and activation of abiraterone acetate in mice and humans. Life Sci 284:119896
     [Google Scholar]
  106. 105. 
    Kobayashi Y, Fukami T, Higuchi R, Nakajima M, Yokoi T. 2012. Metabolic activation by human arylacetamide deacetylase, CYP2E1, and CYP1A2 causes phenacetin-induced methemoglobinemia. Biochem. Pharmacol. 84:1196–206
     [Google Scholar]
  107. 106. 
    Stricker BH, Blok AP, Bronkhorst FB, Van Parys GE, Desmet VJ. 1986. Ketoconazole-associated hepatic injury. A clinicopathological study of 55 cases. J. Hepatol. 3:399–406
     [Google Scholar]
  108. 107. 
    Rodriguez RJ, Acosta D Jr. 1997. N-deacetyl ketoconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes. Toxicology 117:123–31
     [Google Scholar]
  109. 108. 
    Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D. 1983. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J. Clin. Investig. 71:1495–99
     [Google Scholar]
  110. 109. 
    Kurokawa T, Fukami T, Yoshida T, Nakajima M. 2016. Arylacetamide deacetylase is responsible for activation of prasugrel in human and dog. Drug Metab. Dispos. 44:409–16
     [Google Scholar]
  111. 110. 
    Koshimichi H, Tsuda Y, Ishibashi T, Wajima T. 2019. Population pharmacokinetic and exposure-response analyses of baloxavir marboxil in adults and adolescents including patients with influenza. J. Pharm. Sci. 108:1896–904
     [Google Scholar]
  112. 111. 
    Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN 1996. The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics 33:498–507
     [Google Scholar]
  113. 112. 
    Davies HG, Richter RJ, Keifer M, Broomfield CA, Sowalla J et al. 1996. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman, and sarin. Nat. Genet. 14:334–36
     [Google Scholar]
  114. 113. 
    Hioki T, Fukami T, Nakajima M, Yokoi T. 2011. Human paraoxonase 1 is the enzyme responsible for pilocarpine hydrolysis. Drug Metab. Dispos. 39:1345–52
     [Google Scholar]
  115. 114. 
    Tougou K, Nakayama A, Watanabe S, Okuyama Y, Morino A. 1998. Paraoxonase has a major role in the hydrolysis of prulifloxacin (NM441), a prodrug of a new antibacterial agent. Drug Metab. Dispos. 26:355–59
     [Google Scholar]
  116. 115. 
    Ishizuka T, Fujimori I, Nishida A, Sakurai H, Yoshigae Y et al. 2012. Paraoxonase 1 as a major bioactivating hydrolase for olmesartan medoxomil in human blood circulation: molecular identification and contribution to plasma metabolism. Drug Metab. Dispos. 40:374–80
     [Google Scholar]
  117. 116. 
    Ishizuka T, Fujimori I, Kato M, Noji-Sakikawa C, Saito M et al. 2010. Human carboxymethylenebutenolidase as a bioactivating hydrolase of olmesartan medoxomil in liver and intestine. J. Biol. Chem. 285:11892–902
     [Google Scholar]
  118. 117. 
    Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R et al. 2005. Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J. Lipid. Res. 46:1239–47
     [Google Scholar]
  119. 118. 
    Iwamura A, Fukami T, Higuchi R, Nakajima M, Yokoi T. 2012. Human α/β hydrolase domain containing 10 (ABHD10) is responsible enzyme for deglucuronidation of mycophenolic acid acyl-glucuronide in liver. J. Biol. Chem. 287:9240–49
     [Google Scholar]
  120. 119. 
    Spahn-Langguth H, Benet LZ. 1992. Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism?. Drug Metab. Rev. 24:5–47
     [Google Scholar]
  121. 120. 
    Wieland E, Shipkova M, Schellhaas U, Schütz E, Niedmann PD et al. 2000. Induction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects?. Clin. Biochem. 33:107–13
     [Google Scholar]
  122. 121. 
    Miyashita T, Kimura K, Fukami T, Nakajima M, Yokoi T. 2014. Evaluation and mechanistic analysis of the cytotoxicity of the acyl glucuronide of nonsteroidal anti-inflammatory drugs. Drug Metab. Dispos. 42:1–8
     [Google Scholar]
  123. 122. 
    Ito Y, Fukami T, Yokoi T, Nakajima M. 2014. An orphan esterase ABHD10 modulates probenecid acyl glucuronidation in human liver. Drug Metab. Dispos. 42:2109–16
     [Google Scholar]
  124. 123. 
    Fukami T. 2015. Role of human orphan esterases in drug-induced toxicity. Yakugaku Zasshi 135:1235–44
     [Google Scholar]
  125. 124. 
    Oda S, Shirai Y, Akai S, Nakajima A, Tsuneyama K et al. 2017. Toxicological role of an acyl glucuronide metabolite in diclofenac-induced acute liver injury in mice. J. Appl. Toxicol. 37:545–53
     [Google Scholar]
  126. 125. 
    Iwamura A, Watanabe K, Akai S, Nishinosono T, Tsuneyama K et al. 2016. Zomepirac acyl glucuronide is responsible for zomepirac-induced acute kidney injury in mice. Drug Metab. Dispos. 44:888–96
     [Google Scholar]
  127. 126. 
    Cao Y, Qiu T, Kathayat RS, Azizi SA, Thorne AK et al. 2019. ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5. Nat. Chem. Biol. 15:1232–40
     [Google Scholar]
  128. 127. 
    John R, Cashman R. 2005. Some distinctions between flavin-containing and cytochrome P450 monooxygenases. Biochem. Biophys. Res. Commun. 338:599–604
     [Google Scholar]
  129. 128. 
    Oda S, Fukami T, Yokoi T, Nakajima M. 2015. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab. Pharmacokinet. 30:30–51
     [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-052220-105907
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Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development
Annual Review of Pharmacology and Toxicology 62, 405 (2022); https://doi.org/10.1146/annurev-pharmtox-052220-105907
/content/journals/10.1146/annurev-pharmtox-052220-105907
/content/journals/10.1146/annurev-pharmtox-052220-105907
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