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Review

Drug metabolism by flavin-containing monooxygenases of human and mouse

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Pages 167-181 | Received 09 Jul 2016, Accepted 19 Sep 2016, Published online: 29 Sep 2016

References

  • Cashman JR, Zhang J. Human flavin-containing monooxygenases. Annu Rev Pharmacol Toxicol. 2006;46:65–100.
  • Phillips I, Francois A, Shephard E. The Flavin-containing monoooxygenases (FMOs): genetic variation and its consequences for the metabolism of therapeutic drugs. Curr Pharmacogen. 2007;5:292–313.
  • Krueger SK, Williams DE. Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther. 2005;106:357–387.
  • Rendic S, Guengerich FP. Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem Res Toxicol. 2015;28:38–42.
  • Phillips IR, Dolphin CT, Clair P, et al. The molecular biology of the flavin-containing monooxygenases of man. Chem Biol Interact. 1995;96:17–32.
  • Hernandez D, Janmohamed A, Chandan P, et al. Organization and evolution of the flavin-containing monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters. Pharmacogenetics. 2004;14:117–130.
  • Hines RN, Hopp KA, Franco J, et al. Alternative processing of the human FMO6 gene renders transcripts incapable of encoding a functional flavin-containing monooxygenase. Mol Pharmacol. 2002;62:320–325.
  • Ziegler DM. Recent studies on the structure and function of multisubstrate flavin-containing monooxygenases. Annu Rev Pharmacol Toxicol. 1993;33:179–199.
  • Poulsen LL, Ziegler DM. Multisubstrate flavin-containing monooxygenases: applications of mechanism to specificity. Chem Biol Interact. 1995;96:57–73.
  • Ziegler DM. An overview of the mechanism, substrate specificities, and structure of FMOs. Drug Metab Rev. 2002;34:503–511.
  • Kim YM, Ziegler DM. Size limits of thiocarbamides accepted as substrates by human flavin-containing monooxygenase 1. Drug Metab Dispos. 2000;28:1003–1006.
  • Guengerich FP. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol. 2001;14:611–650.
  • Kedderis GL, Rickert DE. Loss of rat liver microsomal cytochrome P-450 during methimazole metabolism. Role of flavin-containing monooxygenase. Drug Metab Dispos. 1985;13:58–61.
  • Cerny MA, Hanzlik RP. Cyclopropylamine inactivation of cytochromes P450: role of metabolic intermediate complexes. Arch Biochem Biophys. 2005;436:265–275.
  • Cashman JR. Some distinctions between flavin-containing and cytochrome P450 monooxygenases. Biochem Biophys Res Commun. 2005;338:599–604.
  • Dolphin C, Shephard EA, Povey S, et al. Cloning, primary sequence, and chromosomal mapping of a human flavin-containing monooxygenase (FMO1). J Biol Chem. 1991;266:12379–12385.
  • Koukouritaki SB, Simpson P, Yeung CK, et al. Human hepatic flavin-containing monooxygenases 1 (FMO1) and 3 (FMO3) developmental expression. Pediatric Res. 2002;51:236–243.
  • Cherrington NJ, Cao Y, Cherrington JW, et al. Physiological factors affecting protein expression of flavin-containing monooxygenases 1, 3 and 5. Xenobiotica. 1998;28:673–682.
  • Janmohamed A, Hernandez D, Phillips IR, et al. Cell-, tissue-, sex- and developmental stage-specific expression of mouse flavin-containing monooxygenases (Fmos). Biochem Pharmacol. 2004;68:73–83.
  • Shephard EA, Chandan P, Stevanovic-Walker M, et al. Alternative promoters and repetitive DNA elements define the species-dependent tissue-specific expression of the FMO1 genes of human and mouse. Biochem J. 2007;406:491–499.
  • Dolphin CT, Cullingford TE, Shephard EA, et al. Differential developmental and tissue-specific regulation of expression of the genes encoding three members of the flavin-containing monooxygenase family of man, FMO1, FMO3 and FMO4. Eur J Biochem. 1996;235:683–689.
  • Yeung CK, Lang DH, Thummel KE, et al. Immunoquantitation of FMO1 in human liver, kidney, and intestine. Drug Metab Dispos. 2000;28:1107–1111.
  • Zhang J, Cashman JR. Quantitative analysis of FMO gene mRNA levels in human tissues. Drug Metab Dispos. 2006;34:19–26.
  • Veeravalli S, Omar BA, Houseman L, et al. The phenotype of a flavin-containing monooyxgenase knockout mouse implicates the drug-metabolizing enzyme FMO1 as a novel regulator of energy balance. Biochem Pharmacol. 2014;90:88–95.
  • Siddens LK, Henderson MC, VanDyke JE, et al. Characterization of mouse flavin-containing monooxygenase transcript levels in lung and liver, and activity of expressed isoforms. Biochem Pharmacol. 2008;75:570–579.
  • Shimizu M, Cashman JR, Yamazaki H. Transient trimethylaminuria related to menstruation. BMC Med Genet. 2007;8:2.
  • Falls JG, Blake BL, Cao Y, et al. Gender differences in hepatic expression of flavin-containing monooxygenase isoforms (FMO1, FMO3, and FMO5) in mice. J Biochem Toxicol. 1995;10:171–177.
  • Fu ZD, Selwyn FP, Cui JY, et al. RNA sequencing quantification of xenobiotic-processing genes in various sections of the intestine in comparison to the liver of male mice. Drug Metab Dispos. 2016;44:842–856.
  • Henderson MC, Siddens LK, Morré JT, et al. Metabolism of the anti-tuberculosis drug ethionamide by mouse and human FMO1, FMO2 and FMO3 and mouse and human lung microsomes. Toxicol Appl Pharmacol. 2008;233:420–427.
  • Hamman MA, Haehner-Daniels BD, Wrighton SA, et al. Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes. Biochem Pharmacol. 2000;60:7–17.
  • Overby LH, Carver GC, Philpot RM. Quantitation and kinetic properties of hepatic microsomal and recombinant flavin-containing monooxygenases 3 and 5 from humans. Chem Biol Interact. 1997;106:29–45.
  • Cashman JR, Zhang J. Interindividual differences of human flavin-containing monooxygenase 3: genetic polymorphisms and functional variation. Drug Metab Dispos. 2002;30:1043–1052.
  • Hines RN. Developmental expression of drug metabolizing enzymes: impact on disposition in neonates and young children. Int J Pharm. 2013;452:3–7.
  • Jakobsson SV, Cintig DL. Studies on the cytochrome P-450-containing mono-oxygenase system in human kidney cortex microsomes. J Pharmacol Exper Ther. 1973;185:226–234.
  • Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exper Ther. 1994;270:414–423.
  • Janmohamed A, Dolphin CT, Phillips IR, et al. Quantification and cellular localization of expression in human skin of genes encoding flavin-containing monooxygenases and cytochromes P450. Biochem Pharmacol. 2001;62:777–786.
  • Rae JM, Johnson MD, Lippman ME, et al. Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exper Ther. 2001;299:849–857.
  • Krusekopf S, Roots I. St. John’s wort and its constituent hyperforin concordantly regulate expression of genes encoding enzymes involved in basic cellular pathways. Pharmacogenet Genomics. 2005;15:817–829.
  • Miller MM, James RA, Richer JK, et al. Progesterone regulated expression of flavin-containing monooxygenase 5 by the B-isoform of progesterone receptors: implications for tamoxifen carcinogenicity. J Clin Endocrinol Metab. 1997;82:2956–2961.
  • Houseman L, Edwards M, Phillips IR, et al. Isolation and culture of mouse hepatocytes: gender-specific gene expression responses to chemical treatments. Methods Mol Biol. 2015;1250:3–12.
  • Guo Y, Cui JY, Lu H, et al. Effect of various diets on the expression of phase-I drug-metabolizing enzymes in livers of mice. Xenobiotica. 2015;45:586–597.
  • Celius T, Roblin S, Harper PA, et al. Aryl hydrocarbon receptor-dependent induction of flavin-containing monooxygenase mRNAs in mouse liver. Drug Metab Dispos. 2008;36:2499–2505.
  • Clement B, Weide M, Ziegler DM. Inhibition of purified and membrane-bound flavin-containing monooxygenase 1 by (N,N-dimethylamino)stilbene carboxylates. Chem Res Toxicol. 1996;9:599–604.
  • Cashman JR, Xiong Y, Lin J, et al. In vitro and in vivo inhibition of human flavin-containing monooxygenase form 3 (FMO3) in the presence of dietary indoles. Biochem Pharmacol. 1999;58:1047–1055.
  • Dolphin CT, Shephard EA, Povey P, et al. Cloning, primary sequence and chromosomal localization of human FMO2, a new member of the flavin-containing mono-oxygenase family. Biochem J. 1992;287:261–267.
  • Cashman JR, Park SB, Berkman CE, et al. Role of hepatic flavin-containing monooxygenase 3 in drug and chemical metabolism in adult humans. Chem Biol Interact. 1995;96:33–46.
  • Rodriguez RJ, Miranda CL. Isoform specificity of N-deacetyl ketoconazole by human and rabbit flavin-containing monooxygenases. Drug Metab Dispos. 2000;28:1083–1086.
  • Rodriguez RJ, Buckholz CJ. Hepatotoxicity of ketoconazole in Sprague-Dawley rats: glutathione depletion, flavin-containing monooxygenases-mediated bioactivation and hepatic covalent binding. Xenobiotica. 2003;33:429–441.
  • Shaffer CL, Gunduz M, Scialis RJ, et al. Metabolism and disposition of a selective α7 nicotinic acetylcholine receptor agonist in humans. Drug Metab Dispos. 2007;35:1188–1195.
  • Lang DH, Rettie AE. In vitro evaluation of potential in vivo probes for human flavin-containing monooxygenase (FMO): metabolism of benzydamine and caffeine by FMO and P450 isoforms. Br J Clin Pharmacol. 2000;50:311–314.
  • Potega A, Dabrowska E, Niemira M, et al. The imidazoacridinone antitumor drug, C-1311, is metabolized by flavin monooxygenases but not by cytochrome P450s. Drug Metab Dispos. 2011;39:1423–1432.
  • Hai X, Adams E, Hoogmartens J, et al. Enantioselective in-line and off-line CE methods for the kinetic study on cimetidine and its chiral metabolites with reference to flavin-containing monooxygenase genetic isoforms. Electrophoresis. 2009;30:1248–1257.
  • Szökő É, Tábi T, Borbás T, et al. Assessment of the N-oxidation of deprenyl, methamphetamine, and amphetamine enantiomers by chiral capillary electrophoresis: an in vitro metabolism study. Electrophoresis. 2004;25:2866–2875.
  • Pike MG, Mays DC, Macomber DW, et al. Metabolism of a disulfiram metabolite, S-methyl N,N-diethyldithiocarbamate, by flavin monooxygenase in human renal microsomes. Drug Metab Dispos. 2001;29:127–132.
  • Joo J, Wu Z, Lee B, et al. In vitro metabolism of an estrogen-related receptor γ modulator, GSK5182, by human liver microsomes and recombinant cytochrome P450s. Biopharm Drug Dispos. 2015;36:163–173.
  • Furnes B, Schlenk D. Evaluation of xenobiotic N- and S-oxidation by variant flavin-containing monooxygenase 1 (FMO1) enzymes. Toxicol Sci. 2004;78:196–203.
  • Mushiroda T, Douya R, Takahara E, et al. The involvement of flavin-containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride, a gastroprokinetic agent: comparison with cisapride and mosapride citrate. Drug Metab Dispos. 2000;28:1231–1237.
  • Usmani KA, Chen WG, Sadeque AJM. Identification of human cytochrome P450 and flavin-containing monooxygenase enzymes involved in the metabolism of lorcaserin, a novel selective human 5-hydroxytryptamine 2C agonist. Drug Metab Dispos. 2012;40:761–771.
  • Ohmi N, Yoshida H, Endo H, et al. S-oxidation of S-methyl-esonarimod by flavin-containing monooxygenases in human liver microsomes. Xenobiotica. 2003;33:1221–1231.
  • Ballard JE, Prueksaritanont T, Tang C. Hepatic metabolism of MK-0457, a potent aurora kinase inhibitor: interspecies comparison and role of human cytochrome P450 and flavin-containing monooxygenase. Drug Metab Dispos. 2007;35:1447–1451.
  • Karanam BV, Hop CECA, Liu DQ, et al. In vitro metabolism of MK-0767 [(±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl) phenyl]methyl]benzamide], a peroxisome proliferator-activated receptor alpha/gamma agonist. I. Role of cytochrome P450, methyltransferases, flavin monooxygenases, and esterases. Drug Metab Dispos. 2004;32:1015–1022.
  • Yu J, Brown DG, Burdette D. In vitro metabolism studies of nomifensine monooxygenation pathways: metabolite identification, reaction phenotyping, and bioactivation mechanism. Drug Metab Dispos. 2010;38:1767–1778.
  • Kajita J, Inano K, Fuse E, et al. Effects of olopatadine, a new antiallergic agent, on human liver microsomal cytochrome P450 activities. Drug Metab Dispos. 2002;30:1504–1511.
  • Xie G, Wong CC, Cheng K-W, et al. Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety. Br J Pharmacol. 2012;167:222–232.
  • Li F, Patterson AD, Krausz KW, et al. Metabolomics reveals the metabolic map of procainamide in humans and mice. Biochem Pharmacol. 2012;83:1435–1444.
  • Miura M, Ohkubo T. In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions. Xenobiotica. 2004;34:1001–1011.
  • Hai X, Nauwelaers T, Busson R, et al. A rapid and sensitive CE method with field-enhanced sample injection and in-capillary derivatization for selenomethionine metabolism catalyzed by flavin-containing monooxygenases. Electrophoresis. 2010;31:3352–3361.
  • Washio T, Arisawa H, Kohsaka K, et al. Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011. Biol Pharm Bull. 2001;24:1263–1266.
  • Parte P, Kupfer D. Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Drug Metab Dispos. 2005;33:1446–1452.
  • Attar M, Dong D, Ling K-HJ, et al. Cytochrome P450 2C8 and flavin-containing monooxygenases are involved in the metabolism of tazarotenic acid in humans. Drug Metab Dispos. 2003;31:476–481.
  • Kousba A, Soll R, Yee S, et al. Cyclic conversion of the novel Src kinase inhibitor [7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (TG100435) and its N-oxide metabolite by flavin-containing monoxygenases and cytochrome P450 reductase. Drug Metab Dispos. 2007;35:2242–2251.
  • Francois AA, Nishida CR, Ortiz De Montellano PR, et al. Human flavin-containing monooxygenase 2.1 catalyzes oxygenation of the antitubercular drugs thiacetazone and ethionamide. Drug Metab Dispos. 2009;37:178–186.
  • Qian L, Ortiz De Montellano PR. Oxidative activation of thiacetazone by the Mycobacterium tuberculosis flavin monooxygenase EtaA and human FMO1 and FMO3. Chem Res Toxicol. 2006;19:443–449.
  • Yanni SB, Annaert PP, Augustijns P, et al. Role of flavin-containing monooxygenase in oxidative metabolism of voriconazole by human liver microsomes. Drug Metab Dispos. 2008;36:1119–1125.
  • Ring BJ, Wrighton SA, Aldridge SL, et al. Flavin-containing monooxygenase-mediated N-oxidation of the M1-muscarinic agonist xanomeline. Drug Metab Dispos. 1999;27:1099–1103.
  • Krueger SK, Martin SR, Yueh M-F, et al. Identification of active flavin-containing monooxygenase isoform 2 in human lung and characterization of expressed protein. Drug Metab Dispos. 2002;30:34–41.
  • Rawden HC, Kokwaro GO, Ward SA, et al. Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes. Br J Clin Pharmacol. 2000;49:313–322.
  • Wagmann L, Meyer MR, Maurer HH. What is the contribution of human FMO3 in the N-oxygenation of selected therapeutic drugs and drugs of abuse? Toxicol Lett. 2016;258:55–70.
  • Salva M, Jansat JM, Martinez-Tobed A, et al. Identification of the human liver enzymes involved in the metabolism of the antimigraine agent almotriptan. Drug Metab Dispos. 2003;31:404–411.
  • Cashman JR, Xiong YN, Xu L, et al. N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication. J Pharmacol Exp Ther. 1999;288:1251–1260.
  • Mayatepek E, Flock B, Zschocke J. Benzydamine metabolism in vivo is impaired in patients with deficiency of flavin-containing monooxygenase 3. Pharmacogenetics. 2004;14:775–777.
  • Störmer E, Roots I, Brockmöller J. Benzydamine N-oxidation as an index reaction reflecting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity. Br J Clin Pharmacol. 2000;50:553–561.
  • Cashman JR, Park SB, Yang ZC, et al. Chemical, enzymatic, and human enantioselective S-oxygenation of cimetidine. Drug Metab Dispos. 1993;21:587–597.
  • Tugnait M, Hawes EM, McKay G, et al. N-oxygenation of clozapine by flavin-containing monooxygenase. Drug Metab Dispos. 1997;25:524–527.
  • Catucci GG, Occhipinti AA, Maffei MM, et al. Effect of human flavin-containing monooxygenase 3 polymorphism on the metabolism of aurora kinase inhibitors. Int J Mol Sci. 2013;14:2707–2716.
  • Wang L, Christopher LJ, Cui D, et al. Identification of the human enzymes involved in the oxidative metabolism of dasatinib: an effective approach for determining metabolite formation kinetics. Drug Metab Dispos. 2008;36:1828–1839.
  • Zhou S, Kestell P, Paxton JW. 6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3. Eur J Drug Metab Pharmacokinet. 2002;27:179–183.
  • Pike MG, Martin YN, Mays DC, et al. Roles of FMO and CYP450 in the metabolism in human liver microsomes of S-methyl-N,N-diethyldithiocarbamate, a disulfiram metabolite. Alcohol Clin Exp Res. 1999;23:1173–1179.
  • Zhou L-P, Tan Z-R, Chen H, et al. Effect of two-linked mutations of the FMO3 gene on itopride metabolism in Chinese healthy volunteers. Eur J Clin Pharmacol. 2014;70:1333–1338.
  • Jacobsen W, Christians U, Benet LZ. In vitro evaluation of the disposition of a novel cysteine protease inhibitor. Drug Metab Dispos. 2000;28:1343–1351.
  • Prueksaritanont T, Lu P, Gorham L, et al. Interspecies comparison and role of human cytochrome P450 and flavin-containing monooxygenase in hepatic metabolism of L-775,606, a potent 5-HT(1D) receptor agonist. Xenobiotica. 2000;30:47–59.
  • Luo JP, Vashishtha SC, Hawes EM, et al. In vitro identification of the human cytochrome p450 enzymes involved in the oxidative metabolism of loxapine. Biopharm Drug Dispos. 2011;32:398–407.
  • Hanlon SP, Camattari A, Abad S, et al. Expression of recombinant human flavin monooxygenase and moclobemide-N-oxide synthesis on multi-mg scale. Chem Commun. 2012;48:6001–6003.
  • Park SB, Jacob P, Benowitz NL, et al. Stereoselective metabolism of (S)-(-)-nicotine in humans: formation of trans-(S)-(-)-nicotine N-1′-oxide. Chem Res Toxicol. 1993;6:880–888.
  • Bloom AJ, Murphy SE, Martinez M, et al. Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption. Pharmacogenet Genomics. 2013;23:62–68.
  • Ring BJ, Catlow J, Lindsay TJ, et al. Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J Pharmacol Exper Ther. 1996;276:658–666.
  • Söderberg MM, Haslemo T, Molden E, et al. Influence of FMO1 and 3 polymorphisms on serum olanzapine and its N-oxide metabolite in psychiatric patients. Pharmacogenomics J. 2013;13:544–550.
  • Jin X, Pybus BS, Marcsisin R, et al. An LC-MS based study of the metabolic profile of primaquine, an 8-aminoquinoline antiparasitic drug, with an in vitro primary human hepatocyte culture model. Eur J Drug Metab Pharmacokinet. 2014;39:139–146.
  • Reid JM, Walker DL, Miller JK, et al. The metabolism of pyrazoloacridine (NSC 366140) by cytochromes P450 and flavin monooxygenase in human liver microsomes. Clin Cancer Res. 2004;10:1471–1480.
  • Chung W-G, Park CS, Roh HK, et al. Oxidation of ranitidine by isozymes of flavin-containing monooxygenase and cytochrome P450. Jpn J Pharmacol. 2000;84:213–220.
  • Pichard-Garcia L, Weaver RJ, Eckett N, et al. The olivacine derivative S 16020 (9-hydroxy-5,6-dimethyl-N-[2-(dimethylamino)ethyl)-6H-pyrido(4,3-B)-carbazole-1-carboxamide) induces CYP1A and its own metabolism in human hepatocytes in primary culture. Drug Metab Dispos. 2004;32:80–88.
  • Lomri N, Yang Z, Cashman JR. Expression in Escherichia coli of the flavin-containing monooxygenase D (form II) from adult human liver: determination of a distinct tertiary amine substrate specificity. Chem Res Toxicol. 1993;6:425–429.
  • Lai WG, Farah N, Moniz GA, et al. A Baeyer-Villiger oxidation specifically catalyzed by human flavin-containing monooxygenase 5. Drug Metab Dispos. 2011;39:61–70.
  • Meng J, Zhong D, Li L, et al. Metabolism of MRX-I, a novel antibacterial oxazolidinone, in humans: the oxidative ring opening of 2,3-Dihydropyridin-4-one catalyzed by non-P450 enzymes. Drug Metab Dispos. 2015;43:646–659.
  • Rettie AE, Lawton MP, Sadeque AJ, et al. Prochiral sulfoxidation as a probe for multiple forms of the microsomal flavin-containing monooxygenase: studies with rabbit FMO1, FMO2, FMO3, and FMO5 expressed in Escherichia coli. Arch Biochem Biophys. 1994;311:369–377.
  • Zhang J, Cerny MA, Lawson M, et al. Functional activity of the mouse flavin-containing monooxygenase forms 1, 3, and 5. J Biochem Mol Toxicol. 2007;21:206–215.
  • Fiorentini F, Geier M, Binda C, et al. Biocatalytic characterization of human FMO5: unearthing Baeyer-Villiger reactions in humans. ACS Chem Biol. 2016;11:1039–1048.
  • Chen GP, Poulsen LL, Ziegler DM. Oxidation of aldehydes catalyzed by pig liver flavin-containing monooxygenase. Drug Metab Dispos. 1995;23:1390–1393.
  • Nakajima M, Yamamoto T, Nunoya K, et al. Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug Metab Dispos. 1996;24:1212–1217.
  • Cashman JR. Role of flavin-containing monooxygenase in drug development. Expert Opin Drug Metab Toxicol. 2008;4:1507–1521.
  • Kitamura S, Sugihara K, Tatsumi K. A unique tertiary amine N-oxide reduction system composed of quinone reductase and heme in rat liver preparations. Drug Metab Dispos. 1999;27:92–97.
  • Kitamura S, Tatsumi K. Involvement of liver aldehyde oxidase in the reduction of nicotinamide N-oxide. Biochem Biophys Res Commun. 1984;120:602–606.
  • Ziegler DM. Flavin-containing monooxygenases: catalytic mechanism and substrate specificities. Drug Metab Rev. 1988;19:1–32.
  • Yamada H, Baba T, Hirata Y, et al. Studies on N-demethylation of methamphetamine by liver microsomes of guinea-pigs and rats: the role of flavin-containing mono-oxygenase and cytochrome P-450 systems. Xenobiotica. 1984;14:861–866.
  • Chiba K, Kobayashi K, Itoh K, et al. N-oxygenation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by the rat liver flavin-containing monooxygenase expressed in yeast cells. Eur J Pharmacol. 1995;293:97–100.
  • Henderson MC, Krueger SK, Siddens LK, et al. S-oxygenation of the thioether organophosphate insecticides phorate and disulfoton by human lung flavin-containing monooxygenase 2. Biochem Pharmacol. 2004;68:959–967.
  • Dolphin CT, Janmohamed A, Smith RL, et al. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet. 1997;17:491–494.
  • Lang DH, Yeung CK, Peter RM, et al. Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: selective catalysis by FMO3. Biochem Pharmacol. 1998;56:1005–1012.
  • Lin J, Cashman JR. Detoxication of tyramine by the flavin-containing monooxygenase: stereoselective formation of the trans oxime. Chem Res Toxicol. 1997;10:842–852.
  • Lin J, Cashman JR. N-oxygenation of phenethylamine to the trans-oxime by adult human liver flavin-containing monooxygenase and retroreduction of phenethylamine hydroxylamine by human liver microsomes. J Pharmacol Exp Ther. 1997;282:1269–1279.
  • Gonzalez Malagon SG, Melidoni AN, Hernandez D, et al. The phenotype of a knockout mouse identifies flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic ageing. Biochem Pharmacol. 2015;96:267–277.
  • Dolphin CT, Beckett DJ, Janmohamed A, et al. The Flavin-containing monooxygenase 2 gene (FMO2) of humans, but not of other primates, encodes a truncated, nonfunctional protein. J Biol Chem. 1998;273:30599–30607.
  • Veeramah KR, Thomas MG, Weale ME, et al. The potentially deleterious functional variant flavin-containing monooxygenase 2*1 is at high frequency throughout sub-Saharan Africa. Pharmacogenet Genomics. 2008;18:877–886.
  • Krueger SK, Siddens LK, Henderson MC, et al. Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics. Pharmacogenet Genomics. 2005;15:245–256.
  • Treacy EP, Akerman BR, Chow LM, et al. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet. 1998;7:839–845.
  • Yamazaki H, Shimizu M. Survey of variants of human flavin-containing monooxygenase 3 (FMO3) and their drug oxidation activities. Biochem Pharmacol. 2013;85:1588–1593.
  • Shephard EA, Treacy EP, Phillips IR. Clinical utility gene card for: trimethylaminuria - update 2014. Eur J Hum Genet. 2015;23. DOI:10.1038/ejhg.2014.226
  • Phillips IR, Shephard EA. Primary Trimethylaminuria. In: GeneReviews at genetests: medicalgenetics information resource (database online). 2015. Copyright University of Washington, Seattle 1993-2016. Available from: www.ncbi.nlm.gov/NBK1103/
  • Phillips IR, Shephard EA. Flavin-containing monooxygenases: mutations, disease and drug response. Trends Pharmacol Sci. 2008;29:294–301.
  • Hernandez D, Addou S, Lee D, et al. Trimethylaminuria and a human FMO3 mutation database. Hum Mutat. 2003;22:209–213.
  • Cashman JR. The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and development. Drug Discov Today. 2004;9:574–581.
  • Koukouritaki SB, Hines RN. Flavin-containing monooxygenase genetic polymorphism: impact on chemical metabolism and drug development. Pharmacogenomics. 2005;6:807–822.
  • Sachse C, Ruschen S, Dettling M, et al. Flavin monooxygenase 3 (FMO3) polymorphism in a white population: allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism. Clin Pharmacol Ther. 1999;66:431–438.
  • Kang J-H, Chung W-G, Lee K-H, et al. Phenotypes of Flavin-containing monooxygenase activity determined by ranitidine N-oxidation are positively correlated with genotypes of linked FMO3 gene mutations in a Korean population. Pharmacogenetics. 2000;10:67–78.
  • Park C-S, Kang J-H, Chung W-G, et al. Ethnic differences in allelic frequency of two Flavin- containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities. Pharmacogenet Genomics. 2002;12:1–4.
  • Allerston CK, Shimizu M, Fujieda M, et al. Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene (FMO3). Pharmacogenet Genomics. 2007;17:827–839.
  • Lattard V, Zhang J, Tran Q, et al. Two new polymorphisms of the FMO3 gene in Caucasian and African-American populations: comparative genetic and functional studies. Drug Metab Dispos. 2003;31:854–860.
  • Shimizu M, Yano H, Nagashima S, et al. Effect of genetic variants of the human Flavin-containing monooxygenase 3 on N- and S-oxygenation activities. Drug Metab Dispos. 2007;35:328–330.
  • Koukouritaki SB, Poch MT, Henderson MC, et al. Identification and functional analysis of common human Flavin-containing monooxygenase 3 genetic variants. J Pharmacol Exper Ther. 2007;320:266–273.
  • Koukouritaki SB, Poch MT, Cabacungan ET, et al. Discovery of novel flavin-containing monooxygenase 3 (FMO3) single nucleotide polymorphisms and functional analysis of upstream haplotype variants. Mol Pharmacol. 2005;68:383–392.
  • Shimizu M, Shiraishi A, Sato A, et al. Potential for drug interactions mediated by polymorphic flavin-containing monooxygenase 3 in human livers. Drug Metab Pharmacokinet. 2015;30:70–74.
  • Ryu S-D, Yi H-G, Cha Y-N, et al. Flavin-containing monooxygenase activity can be inhibited by nitric oxide-mediated S-nitrosylation. Life Sci. 2004;75:2559–2572.
  • Nagashima S, Shimizu M, Yano H, et al. Inter-individual variation in flavin-containing monooxygenase 3 in livers from Japanese: correlation with hepatic transcription factors. Drug Metab Pharmacokinet. 2009;24:218–225.
  • Furnes B, Feng J, Sommer SS, et al. Identification of novel variants of the flavin-containing monooxygenase gene family in African Americans. Drug Metab Dispos. 2003;31:187–193.
  • Hines RN, Luo Z, Hopp KA, et al. Genetic variability at the human FMO1 locus: significance of a basal promoter yin yang 1 element polymorphism (FMO1*6). J Pharmacol Exper Ther. 2003;306:1210–1218.
  • Hisamuddin IM, Wehbi MA, Chao A, et al. Genetic polymorphisms of human flavin monooxygenase 3 in sulindac-mediated primary chemoprevention of familial adenomatous polyposis. Clin Cancer Res. 2004;10:8357–8362.
  • Hisamuddin IM, Wehbi MA, Schmotzer B, et al. Genetic polymorphisms of flavin monooxygenase 3 in sulindac-induced regression of colorectal adenomas in familial adenomatous polyposis. Cancer Epidemiol Biomarkers Prev. 2005;14:2366–2369.
  • Korprasertthaworn P, Polasek TM, Sorich MJ, et al. In vitro characterization of the human liver microsomal kinetics and reaction phenotyping of olanzapine metabolism. Drug Metab Dispos. 2015;43:1806–1814.
  • Söderberg MM, Dahl M-L. Pharmacogenetics of olanzapine metabolism. Pharmacogenomics. 2013;14:1319–1336.
  • Okubo M, Narita M, Murayama N, et al. Individual differences in in vitro and in vivo metabolic clearances of the antipsychotic drug olanzapine from non-smoking and smoking Japanese subjects genotyped for cytochrome P4502D6 and flavincontaining monooxygenase 3. Hum Psychopharmacol. 2016;31:83–92.
  • Cashman JR, Zhang J, Nelson MR, et al. Analysis of flavin-containing monooxygenase 3 genotype data in populations administered the anti-schizophrenia agent olanzapine. Drug Metab Lett. 2008;2:100–114.
  • Yamanaka H, Nakajima M, Nishimura K, et al. Metabolic profile of nicotine in subjects whose CYP2A6 gene is deleted. Eur J Pharm Sci. 2004;22:419–425.
  • Hernandez D, Janmohamed A, Chandan P, et al. Deletion of the mouse Fmo1 gene results in enhanced pharmacological behavioural responses to imipramine. Pharmacogenet Genomics. 2009;19:289–299.
  • Shephard EA, Phillips IR. The potential of knockout mouse lines in defining the role of flavin-containing monooxygenases in drug metabolism. Expert Opin Drug Metab Toxicol. 2010;6:1083–1094.
  • Palmer A, Leykam V, Larkin A, et al. Metabolism and pharmacokinetics of the anti-tuberculosis drug ethionamide in a Flavin-containing monooxygenase null mouse. Pharmaceuticals. 2012;5:1147–1159.
  • Vannelli TA, Dykman A, Ortiz de Montellano PR. The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase. J Biol Chem. 2002;277:12824–12829.

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