The potential of knockout mouse lines in defining the role of flavin-containing monooxygenases in drug metabolism

Expert Opinion on Drug Metabolism and Toxicology

Volumn 6, Issue 9, 2010, Pages 1083-1094

  Shephard, Elizabeth A ^a   Phillips, Ian R ^b  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

Clozapine; Drug metabolism; FMO; Imipramine; Knockout mouse; Retro reduction; Src kinase inhibitor; Tamoxifen

Indexed keywords

[7 (2,6 DICHLOROPHENYL) 5 METHYLBENZO[1,2,4]TRIAZIN 3 YL] [4 2(2 PYRROLIDIN 1 YL ETHOXY)PHENYL]AMINE; ANTINEOPLASTIC AGENT; BENZYDAMINE; CLOZAPINE; CYTOCHROME P450; DEBRISOQUINE; DESIPRAMINE; DIMETHYLANILINE MONOOXYGENASE; DIMETHYLANILINE MONOOXYGENASE 1; DIMETHYLANILINE MONOOXYGENASE 3; IMIPRAMINE; N OXIDE [7 (2,6 DICHLOROPHENYL) 5 METHYLBENZO[1,2,4]TRIAZIN 3 YL] [4 [2 (1 OXY PYRROLIDIN 1 YL)ETHOXY]PHENYL]AMINE; NONSTEROID ANTIINFLAMMATORY AGENT; NORCLOZAPINE; RECOMBINANT ENZYME; SULINDAC; TAMOXIFEN; TG 100435; TG 100855; THIAMAZOLE; UNCLASSIFIED DRUG;

DRUG METABOLISM; ENZYME ACTIVITY; ENZYME DEGRADATION; ENZYME MECHANISM; GENE DELETION; GENE EXPRESSION; GENETIC VARIABILITY; HUMAN; KNOCKOUT MOUSE; NONHUMAN; PROTEIN EXPRESSION; REVIEW; TISSUE DISTRIBUTION;

ANIMALS; CYTOCHROME P-450 ENZYME SYSTEM; GENETIC VARIATION; HUMANS; IMIPRAMINE; MALE; MICE; MICE, KNOCKOUT; OXYGENASES; PHARMACEUTICAL PREPARATIONS; POLYMORPHISM, GENETIC; POLYMORPHISM, SINGLE NUCLEOTIDE;

EID: 77955835622     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425255.2010.503705     Document Type: Review

References (82)

1. Krueger SK, Williams DE. Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther 2005;106:357-387
2. Cashman JR, Zhang J. Human flavin-containing monooxygenases. Annu Rev Pharmacol Toxicol 2006;46:65-100
3. Phillips IR, Francois AA, Shephard EA. The flavin-containing monoooxygenases (FMOs): genetic variation and its consequences for the metabolism of therapeutic drugs. Curr Pharmacogenomics 2007;5:292-313
4. Ziegler DM. Bioactivation of xenobiotics by flavin-containing monooxygenases. Adv Exp Med Biol 1991;283:41-50
5. 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
6. Francois AA, Nishida CR, 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
7. Henderson MC, Siddens LK, Morre 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
8. Ziegler DM. Recent studies on the structure and function of multisubstrate flavin-containing monooxygenases. Annu Rev Pharmacol Toxicol 1993;33:179-199
9. 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
10. 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
11. 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
12. Shephard AE, Dolphin CT, Fox MF, et al. Localization of genes encoding three distinct flavin-containing monooxygenases to human chromosome 1q. Genomics 1993;16:85-89
13. McCombie RR, Dolphin CT, Povey S, et al. Localization of human flavin-containing monooxygenase genes FMO2 and FMO5 to chromosome 1q. Genomics 1996;34:426-429
14. 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
15. Koukouritaki SB, Simpson P, Yeung CK, et al. Human hepatic flavin-containing monooxygenases 1 (FMO1) and 3 (FMO3) developmental expression. Pediatr Res 2002;51:236-243
16. Lawton MP, Gasser R, Tynes RE, et al. The flavin-containing monooxygenase enzymes expressed in rabbit liver and lung are products of related but distinctly different genes. J Biol Chem 1990;265:5855-5861
17. Gasser R, Tynes RE, Lawton MP, et al. The flavin-containing monooxygenase expressed in pig liver: primary sequence, distribution, and evidence for a single gene. Biochemistry 1990;29:119-124
18. 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
19. Lattard V, Longin-Sauvageon C, Benoit E. Cloning, sequencing and tissue distribution of rat flavin-containing monooxygenase 4: two different forms are produced by tissue-specific alternative splicing. Mol Pharmacol 2003;63:253-261
20. Stevens JC, Melton RJ, Zaya MJ, Engel LC. Expression and characterization of functional dog flavin-containing monooxygenase 1. Mol Pharmacol 2003;63:271-275
21. 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
22. Yeung CK, Lang DH, Thummel KE, Rettie AE. Immunoquantitation of FMO1 in human liver, kidney, and intestine. Drug Metab Dispos 2000;28:1107-1111
23. Jakobsson SV, Cintig DL. Studies on the cytochrome P-450-containing mono-oxygenase system in human kidney cortex microsomes. J Pharmacol Exp Ther 1973;185:226-234
24. 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 Exp Ther 1994;270:414-423
25. 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
26. Whetstine JR, Yueh M, McCarver DG, et al. Ethnic differences in human flavin-containing monooxygenase 2 (FMO2) polymorphisms: detection of expressed protein in African-Americans. Toxicol Appl Pharmacol 2000;168:216-224
27. Veeramah K, 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
28. Phillips IR, Shephard EA. Flavin-containing monooxygenases: mutations, disease and drug response. Trends Pharmacol Sci 2008;29:294-301
29. Janmohamed A, Hernandez D, Phillips IR, Shephard EA. Cell-, tissue-, sex- and developmental stage-specific expression of mouse flavin-containing monooxygenases (Fmos). Biochem Pharmacol 2004;68:73-83
30. Koukouritaki SB, Hines RN. Flavin-containing monooxygenase genetic polymorphism: impact on chemical metabolism and drug development. Pharmacogenomics 2005;6:807-822
31. Furnes B, Feng J, Sommer SS, Schlenk D. Identification of novel variants of the flavin-containing monooxygenase gene family in African Americans. Drug Metab Dispos 2003;31:187-193
32. 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
33. Phillips IR, Shephard EA. Trimethylaminuria. In: Gene reviews at genetests: medical genetics information resource (database online) copyright, University of Washington, Seattle 1997-2007 Available from: http://www. genetests.org, 2007
34. Hernandez D, Addou S, Lee D, et al. Trimethylaminuria and a human FMO3 mutation database. Hum Mutat 2003;22:209-213
35. 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
36. Treacy EP, Akerman BR, Chow LML, et al. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet 1998;7:839-845
37. Mitchell SC, Smith RL. Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos 2001;29:517-521
38. 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
39. Brunelle A, Bi YA, Lin J, et al. Characterization of two human flavin-containing monooxygenase (form 3) enzymes expressed in Escherichia coli as maltose binding protein fusions. Drug Metab Dispos 1997;25:1001-1007
40. Cashman JR. The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and development. Drug Discov Today 2004;9:574-581
41. 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
42. Kang JH, Chung WG, Lee KH, et al. Phenotypes of flavin-containing monooxygenase activity determined by ranitidine N-oxidation are positively correlated with genotypes of linked FM03 gene mutations in a Korean population. Pharmacogenetics 2000;10:67-78
43. Cashman JR, Zhang J, Leushner J, Braun A. Population distribution of human flavin-containing monooxygenase form 3: gene polymorphisms. Drug Metab Dispos 2001;29:1629-1637
44. Park CS, Kang JH, Chung WG, 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. Pharmacogenetics 2002;12:77-80
45. 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
46. 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
47. 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
48. Koukouritaki SB, Poch MT, Henderson MC, et al. Identification and functional analysis of common human flavin-containing monooxygenase genetic variants. J Pharmacol Exp Ther 2007;320:266-273
49. Kobayashi S, Kim J, Lawley H, et al. Identification of a novel D132H missense mutation in the flavin-containing monoosygenase 3 gene in trimethylaminuria. J Invest Dermatol 2001;117:789
50. 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
51. 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
52. Cashman JR. Role of flavin-containing monooxygenase in drug development. Expert Opin Drug Metab Toxicol 2008;4:1507-1521
53. Ziegler DM. Functional groups activated via flavin-containing monooxygenases. In: Miners JO, Birkett DJ, Drew R, editors, Microsomes and drug oxidations. Taylor and Francis, London; 1988. p. 297-304
54. Hernandez D, Chandan P, Janmohamed A, et al. Deletion of genes from the mouse genome using Cre/loxP technology. Methods Mol Biol 2006;320:307-319
55. 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
56. Nelson JC, Jatlow PI, Quinlan DM. Subjective complaints during desipramine treatment. Relative importance of plasma drug concentrations and the severity of depression. Arch Gen Psychiatry 1984;41:55-59
57. Nagy A, Hansen T. The kinetics of imipramine-N-oxide in man. Acta Pharmacol Toxicol (Copenh) 1978;42:58-67
58. Rapp W, Noren MB, Pedersen F. Comparative trial of imipramine N-oxide and imipramine in the treatment of out-patients with depressive syndromes. Acta Psychiatr Scand 1973;49:77-90
59. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009;41:89-295
60. Devane CL, Wolin RE, Rovere RA, et al. Excessive plasma concentration of tricyclic antidepressants resulting from usual doses: a report of six cases. J Clin Psychiatry 1981;42:143-147
61. Garvey MJ, Tuason VB, Johnson RA, et al. Elevated plasma tricyclic levels with therapeutic doses of imipramine. Am J Psychiatry 1984;141:853-856
62. Lemoine A, Gautier JC, Azoulay D, et al. Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver. Mol Pharmacol 1993;43:827-832
63. Brosen K, Zeugin T, Meyer UA. Role of P450IID6, the target of the sparteine-debrisoquin oxidation polymorphism, in the metabolism of imipramine. Clin Pharmacol Ther 1991;49:609-617
64. Rouer E, Lemoine T, Cresteil P, et al. Effects of genetic of chemically induced diabetes on imipramine metabolism: respective involvement of flavin monooxygenase and cytochrome P-450-dependent monooxygenases. Drug Metab Dispos 1987;15:524-528
65. Koyama E, Kikuchi Y, Echizen H, et al. Simultaneous high-performance liquid chromatography-electrochemical detection determination of imipramine, desipramine, their 2-hydroxylated metabolites, and imipramine N-oxide in human plasma and urine: preliminary application to oxidation pharmacogenetics. Ther Drug Monit 1993;15:224-235
66. Pirmohamed M, Williams D, Madden S, et al. Metabolism and bioactivation of clozapine by human liver in vitro. J Pharmacol Exp Ther 1995;272:984-990
67. Tugnait M, Hawes EM, McKay G, et al. N-oxygenation of clozapine by flavin-containing monooxygenase. Drug Metab Dispos 1997;25:524-527
68. Fang J. Metabolism of clozapine by rat brain: the role of flavin-containing monooxygenase (FMO) and cytochrome P450 enzymes. Eur J Drug Metab Pharmacokinet 2000;25:109-114
69. Fang J, Coutts RT, McKenna KF, Baker GB. Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine. Naunyn Schmiedebergs Arch Pharmacol 1998;358:592-599
70. Jaquenoud Sirot E, Knezevic B, Morena GP, et al. ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol 2009;29:319-326
71. Zhang WV, D'Esposito F, Edwards RJ, et al. Interindividual variation in relative CYP1A2/3A4 phenotype influences susceptibility of clozapine oxidation to cytochrome P450-specific inhibition in human hepatic microsomes. Drug Metab Dispos 2008;36:2547-2555
72. Noronha G, Barrett K, Boccia A, et al. Discovery of [7-(2,6- dichlorophenyl)-5- methylbenzo [1,2,4]triazin-3-yl]-[4-(2- pyrrolidin-1- ylethoxy)phenyl]amine - a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays. Bioorg Med Chem Lett 2007;17:602-608
73. Hu SX, Soll R, Yee S, et al. Metabolism and pharmacokinetics of a novel Src kinase inhibitor TG100435 ([7-(2,6-dichloro-phenyl)-5-methyl-benzo [1,2,4]triazin-3-yl]-[4-(2-pyrroli din-1-yl-ethoxy)-phenyl]-amine) and its active N-oxide metabolite TG100855 ([7-(2,6-dichloro-phenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-{4-[2-(1-oxy as pyrrolidin-1-yl)-ethoxy]-phenyl}-amine). Drug Metab Dispos 2007;35:929-936
74. Kousba A, Soll R, Yee S, Martin M. 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
75. 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 FM04. Eur J Biochem 1996;235:683-689
76. 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
77. Krueger SK, Vandyke JE, Williams DE, Hines RN. The role of flavin-containing monooxygenase (FMO) in the metabolism of tamoxifen and other tertiary amines. Drug Metab Rev 2006;38:139-147
78. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004;310:1062-1075
79. Kim SY, Laxmi YR, Suzuki N, et al. Formation of tamoxifen-DNA adducts via O-sulfonation, not O-acetylation, of alpha-hydroxytamoxifen in rat and human livers. Drug Metab Dispos 2005;33:1673-1678
80. Wegman P, Elingarami S, Carstensen J, et al. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 2007;9:R7
81. Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005;23:9312-9318
82. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004;329:15-19 (Pubitemid 38869995)