Flavin-containing monooxygenase genetic polymorphism: Impact on chemical metabolism and drug development

Pharmacogenomics

Volumn 6, Issue 8, 2005, Pages 807-822

  Koukouritaki, Sevasti B ^a   Hines, Ronald N ^a  

^a MEDICAL COLLEGE OF WISCONSIN   (United States)

Author keywords

Developmental pharmacology; Drug development; Flavin containing monooxygenase; Gene regulation; Genetic polymorphisms

Indexed keywords

BROMPHENIRAMINE; CLOZAPINE; CLOZAPINE N OXIDE; CYTOCHROME P450 1A2; CYTOCHROME P450 2C; CYTOCHROME P450 3A4; DIMETHYLANILINE MONOOXYGENASE; DIMETHYLANILINE MONOOXYGENASE 1; DIMETHYLANILINE MONOOXYGENASE 2; DIMETHYLANILINE MONOOXYGENASE 3; DIMETHYLANILINE MONOOXYGENASE 4; DIMETHYLANILINE MONOOXYGENASE 5; IMIPRAMINE; MESSENGER RNA; NEUROLEPTIC AGENT; OXYGENASE; PARAXANTHINE; PHENOTHIAZINE; PROMETHAZINE; RANITIDINE; RANITIDINE N OXIDE; SULINDAC; THEOBROMINE; THIAMAZOLE; THIOBENZAMIDE; UNCLASSIFIED DRUG;

ADENOMATOUS POLYP; ALLELE; AMINO ACID SUBSTITUTION; CELLULAR DISTRIBUTION; DRUG CLEARANCE; DRUG EFFICACY; DRUG METABOLISM; DRUG OXIDATION; DRUG RESPONSE; ENZYME SPECIFICITY; ENZYME STRUCTURE; GENE FREQUENCY; GENE LOCUS; GENE MUTATION; GENETIC POLYMORPHISM; GENETIC VARIABILITY; HUMAN; NONHUMAN; NUCLEOTIDE SEQUENCE; PHARMACOGENETICS; PROTEIN EXPRESSION; PROTEIN FAMILY; PROTEIN LOCALIZATION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM;

DRUG DESIGN; HUMANS; ISOENZYMES; MONOAMINE OXIDASE; PHARMACEUTICAL PREPARATIONS; PHARMACOLOGY; POLYMORPHISM, GENETIC; VARIATION (GENETICS);

EID: 28444441585     PISSN: 14622416     EISSN: 17448042     Source Type: Journal    
DOI: 10.2217/14622416.6.8.807     Document Type: Review

References (85)

1. Ziegler DM: Microsomal flavin-containing monooxygenase: oxygenation of nucleophilic and sulfur compounds. In: Enzymatic Basis of Detoxication. Jakoby WB (Ed.), Academic Press, Inc., New York City, NC, USA, 201-227 (1980).
2. Ziegler DM, Mitchell CH: Microsomal oxidase IV: properties of a mixed-function amine oxidase isolated from pig liver microsomes. Arch. Biochem. Biophys. 150, 116-125 (1972).
3. Masters BSS, Ziegler DM: The distinct nature and function of NADPH-cytochrome c reductase and the NADPH-dependent mixed-function amine oxidase of porcine liver microsomes. Arch. Biochem. Biophys. 145, 358-364 (1971).
4. Cashman JR: Flavin monooxygenases. In: Enzyme systems that metabolize drugs and other xenobiotics. Ionnides C (Ed.), John Wiley & Sons, Inc., Indianapolis, IN, USA 67-93 (2002).
5. Suh J-K, Poulsen LL, Ziegler DM, Robertus JD: Redox regulation of yeast flavin-containing monooxygenase. Arch. Biochem. Biophys. 381, 317-322 (2000).
6. Peters LD, Livingstone DR, Shehin S, Hines RN, Schlenk D: Characterization of hepatic flavin monooxygenase from the turbot (Scophthalmus maximus L.). Xenobiotica 25, 121-131 (1995).
7. Krueger SK, Williams DE: Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol. Ther. 106, 357-387 (2005).
8. Lawton MP, Philpot RM: Molecular genetics of the flavin-dependent monooxygenases. Pharmacogenetics 3, 40-44 (1993).
9. Lawton MP, Cashman JR, Cresteil T et al.: A nomenclature for the mammalian flavin-containing monooxygenase gene family based on amino acid sequence identities. Arch. Biochem. Biophys. 308, 254-257 (1994).
10. Phillips IR, Dolphin CT, Clair P et al.: The molecular biology of the flavin-containing monooxygenases of man. Chem. Biol. Interact. 96, 17-32 (1995).
11. Hines RN, Hopp KA, Franco J, Saeian K, Begun FP: Alternative processing of the human hepatic FMO6 gene renders transcripts incapable of encoding a functional flavin-containing monooxygenase. Mol. Pharmacol. 62, 320-325 (2002).
12. Hernandez D, Janmohamed A, Chandan P, Phillips IR, Shephard EA: Organization and evolution of the flavin-containing monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters. Pharmacogenetics 14, 117-130 (2004).
13. Ziegler DM: An overview of the mechanism, substrate specificities, and structure of FMOs. Drug Metab. Rev. 34, 503-511 (2002).
14. Kim YM, Ziegler DM: Size limits of thiocarbamides accepted as substrates by human flavin-containing monooxygenase. Drug Metab. Dispos. 28, 1003-1006 (2000).
15. 14C-aldicarb. Pesticide Biochem. Physiol. 73, 67-73 (2002).
16. Clement B, Lustig KL, Ziegler DM: Oxidation of desmethylpromethazine catalyzed by pig liver flavin-containing monooxygenase: Number and nature of metabolites. Drug Metab. Dispos. 21, 24-29 (1993).
17. Cashman JR, Celestial JR, Leach A, Newdoll J, Park SB: Tertiary amines related to brompheniramine: Preferred conformations for N-oxygenation by the hog liver flavin-containing monooxygenase. Pharm. Res. 10, 1097-11105 (1993).
18. Poulsen LL, Taylor K, Williams DE, Masters BSS, Ziegler DM: Substrate specificity of the rabbit lung flavin-containing monooxygenase for amines: Oxidation products of primary alkylamines. Mol. Pharmacol. 30, 680-685 (1986).
19. 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. 56, 1005-1012 (1998).
20. Park SB, Jacob P 3rd, Benowitz NL, Cashman JR: Stereoselective metabolism of (S)-(-)-nicotine in humans: Formation of trans-(S)-(-)-nicotine N-1′-oxide. Chem. Res. Toxicol. 6, 880-888 (1993).
21. Cashman JR, Park SB, Yang Z-C et al.: Chemical, enzymatic, and human enantioselective S-oxygenation of cimetidine. Drug Metab. Dispos. 21, 587-597 (1993).
22. 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 populations. Pharmacogenetics 10, 67-78 (2000).
23. Itagaki K, Carver GT, Philpot RM: Expression and characterization of a modified flavin-containing monooxygenase 4 from humans. J. Biol. Chem. 271, 20102-20107 (1996).
24. Dolphin CT, Cullingford TE, Shephard EA, Smith RL, Phillips IR: Differential developmental and tissue-specific regulation of expression of the genes encoding three members of the flavin-containing monooxygenase family of man, FMO1, FM03 and FM04. Eur. J. Biochem. 235, 683-689 (1996).
25. Overby LH, Buckpitt AR, Lawton MP, Atta-Asafo-Adjei E, Schulze J, Philpot RM: Characterization of flavin-containing monooxygenase 5 (FMO5) cloned from human and guinea-pig: Evidence that the unique catalytic properties of FMO5 are not confined to the rabbit ortholog. Arch. Biochem. Biophys. 317, 275-284 (1995).
26. Fisher MB, Lawton MP, Atta-Asafo-Adjei E, Philpot RM, Rettie AE: Selectivity of flavin-containing monooxygenase 5 for the (S)-sulfoxidation of short-chain aralkyl sulfides. Drug Metab. Dispos. 23, 1431-1433 (1995).
27. 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. 106, 29-45 (1997).
28. Yeung CK, Lang DH, Thummel KE, Rettie AE: Immunoquantitation of FMO1 in human liver, kidney, and intestine. Drug Metab. Dispos. 28, 1107-1111 (2000).
29. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP: Interindividual variations in human liver cytochrome P450 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. 270, 414-423 (1994).
30. Krause RJ, Lash LH, Elfarra AA: Human kidney flavin-containing monooxygenases and their potential roles in cysteine S-conjugate metabolism and nephrotoxicity. J. Pharmacol. Exp. Ther. 304, 185-191 (2003).
31. Koukouritaki SB, Simpson P, Yeung CK, Rettie AE, Hines RN: Human hepatic flavin-containing monooxygenase 1 (FMO1) and 3 (FMO3) developmental expression. Pediatric Res. 51, 236-243 (2002).
32. Lomri N, Gu Q, Cashman JR: Molecular cloning of the flavin-containing monooxygenase (form II) cDNA from adult human liver. Proc. Natl Acad. Sci. USA 89, 1685-1689 (1992).
33. Luo Z, Hines RN: Further characterization of the major and minor rabbit FMO1 promoters and identification of both positive and negative distal regulatory elements. Arch. Biochem. Biophys. 346, 96-104 (1997).
34. Furnes B, Feng J, Sommer S, Schlenk D: Identification of novel variants of the flavin-containing monooxygenase gene family in African-Americans. Drug Metab. Dispos. 31, 187-193 (2003).
35. Furnes B, Schlenk D: Evaluation of Xenobiotic N- and S-oxidation by variant flavin-containing monooxygenase 1 (FMO1) enzymes. Toxicol. Sci. 78, 196-203 (2004).
36. Hines RN, Luo Z, Hopp KA, Cabacungan ET, Koukouritaki SB, McCarver DG: Genetic variability at the human FMO1 locus: significance of a yin yang 1 element polymorphism (FMO1*6). J. Pharmacol. Exp. Ther. 306, 1210-1218 (2003).
37. Luo Z, Hines RN: Regulation of flavin-containing monooxygenase 1 (FMO1) expression by yin yang 1 (YY1) and hepatic nuclear factors 1 (HNF1) and 4 (HNF4). Mol. Pharmacol. 60, 1421-1430 (2001).
38. Lattard V, Zhang J, Cashman JR: Alternative processing events in human FMO genes. Mol. Pharmacol. 65, 1517-1525 (2004).
39. Henikoff S, Henikoff JG: Amino acid substitution matrices from protein blocks. Proc. Natl Acad. Sci. USA 89, 10915-10919 (1992).
40. Lawton MP, Gasser R, Tynes RE, Hodgson E, Philpot RM: The flavin-containing monooxygenase enzymes expressed in rabbit liver and lung are products of related but distinctly different genes. J. Biol. Chem. 265, 5855-5861 (1990).
41. Nikbakht KN, Lawton MP, Philpot RM: Guinea-pig or rabbit lung flavin-containing monooxygenases with distinct mobilities in SDS-PAGE are allelic variants that differ in primary structure at only two positions. Pharmacogenetics 2, 207-216 (1992).
42. Yueh MF, Krueger SK, Williams DE: Pulmonary flavin-containing monooxygenase (FMO) in Rhesus macaque: Expression of FMO2 protein, mRNA and analysis of the cDNA. Biochim. Biophys. Acta Gene Struct. Expression 1350, 267-271 (1997).
43. Overby L, Nishio SJ, Lawton MP, Plopper CG, Philpot RM: Cellular localization of flavin-containing monooxygenase in rabbit lung. Exp. Lung Res. 18, 131-144 (1992).
44. Shehin-Johnson SE, Williams DE, Larsen-Su S, Stresser DM, Hines RN: Tissue-specific expression of flavin-containing monooxygenase (FMO) forms 1 and 2 in the rabbit. J. Pharmacol. Exp. Ther. 272, 1293-1299 (1995).
45. 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, non-functional protein. J. Biol. Chem. 273, 30599-30607 (1998).
46. Krueger SK, Siddens LK, Henderson MC et al.: Haplotype and functional analysis of four flavin-containing monooxygenase 2 (FMO2) polymorphisms in Hispanics. Pharmacogenetics 15, 245-256 (2005).
47. Whetstine JR, Yueh M-F, Hopp KA et al.: Ethnic differences in human flavin-containing monooxygenase 2 (FMO2) polymorphisms: Detection of expressed protein in African-Americans. Toxicol. Appl. Pharmacol. 168, 216-224 (2000).
48. Garnier J, Osguthorpe DJ, Robson B: Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J. Mol. Biol. 120, 97-120 (1978).
49. Krueger SK, Martin SR, Yueh M-F, Pereira CB, Williams DE: Identification of active flavin-containing monooxygenase isoform 2 in human lung and characterization of expressed protein. Drug Metab. Dispos. 30, 34-41 (2002).
50. Krueger SK, Williams DE, Yueh M-F et al.: Genetic polymorphism of flavin-containing monooxygenase (FMO). Drug Metab. Rev. 34, 519-528 (2002).
51. Krueger SK, Siddens LK, Martin SR et al.: Differences in FMO2*1 allelic frequency between Hispanics of Puerto Rican and Mexican descent. Drug Metab. Dispos. 32, 1337-1340 (2004).
52. Cashman JR, Zhang J: Interindividual differences of human flavin-containing monooxygenase 3: genetic polymorphisms and functional variation. Drug Metab. Dispos. 30, 1043-1052 (2002).
53. Mitchell SC, Smith RL: Trimethylaminuria: the fish malodor syndrome. Drug Metab. Dispos. 29, 517-521 (2001).
54. Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR: A missense mutation in flavin-containing monooxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nature Genet. 17, 491-494 (1997).
55. Forrest SM, Knight M, Akerman BR, Cashman JR, Treacy EP: A novel deletion in the flavin-containing monooxygenase gene (FMO3) in a Greek patient with trimethylaminuria. Pharmacogenetics 11, 169-174 (2001).
56. Zhang J, Tran Q, Lattard V, Cashman JR: Deleterious mutations in the flavin-containing monooxygenase 3 (FMO3) gene causing trimethylaminuria. Pharmacogenetics 13, 495-500 (2003).
57. Mazon RA, Gil-Setas A, Berrade ZS et al.: Primary trimethylaminuria or fish odor syndrome. A novel mutation in the first documented case in Spain. Med. Clin. (Barc.) 120, 219-221 (2003).
58. Akerman BR, Lemass H, Chow LML et al.: Trimethylaminuria is caused by mutations of the FMO3 gene in a North American cohort. Mol. Genet. Metab. 68, 24-31 (1999).
59. Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR: Compound heterozygosity for missense mutations in the flavin-containing monooxygenase 3 (FMO3) gene in patients with fish-odor syndrome. Pharmacogenetics 10, 799-807 (2000).
60. Cashman JR, Bi YA, Lin J et al.: Human flavin-containing monooxygenase form 3: cDNA expression of the enzymes containing amino acid substitutions observed in individuals with trimethylaminuria. Chem. Res. Toxicol. 10, 837-841 (1997).
61. Murphy HC, Dolphin CT, Janmohamed A et al.: A novel mutation in the flavin-containing monooxygenase 3 gene, FMO3, that causes fish-odour syndrome; activity of the mutant enzyme assessed by proton NMR spectroscopy. Pharmacogenetics 10, 439-451 (2000).
62. Basarab T, Ashton GHS, Menage HD, McGrath JA: Sequence variations in the flavin-containing monooxygenase 3 gene (FMO3) in fish odour syndrome. Brit. J. Dermatol. 140, 164-167 (1999).
63. Park C-S, Chung W-G, Kang J-H, Roh H-K, Lee K-H, Cha Y-N: Phenotyping of flavin-containing monooxygenase using caffeine metabolism and genotyping of FMO3 gene in a Korean population. Pharmacogenetics 9, 155-164 (1999).
64. Fujieda M, Yamazaki H, Togashi M, Saito T, Kamataki T: Two novel single nucleotide polymorphisms (SNPs) of the FMO3 gene in Japanese. Drug Metab. Pharmacokin. 18, SNP35 (333)-SNP37 (335) (2003).
65. Zschocke J, Kohlmüeller D, Quak E, Meissner T, Hoffmann GF, Mayatepek E: Mild trimethylaminuria caused by common variants in FMO3 gene. Lancet 354, 834-835 (1999).
66. 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. 7, 839-845 (1998).
67. Akerman BR, Forrest S, Chow L, Youil R, Knight M, Treacy EP: Two novel mutations of the FMO3 gene in a proband with trimethylaminuria. Hum. Mut. 13, 376-379 (1999).
68. Mayatepek E, Kohlmüeller D: Transient trimethylaminuria in childhood. Acta Paediatr. 87, 1205-1207 (1998).
69. Cashman JR, Camp K, Fennessey PV et al.: Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Curr. Drug Metab. 4, 151-170 (2003).
70. 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. 25, 1001-1007 (1997).
71. Cashman JR, Akerman BR, Forrest SM, Treacy EP: Population-specific polymorphisms of the human FMO3 gene: Significance for detoxication. Drug Metab. Dispos. 28, 169-173 (2000).
72. Lattard V, Zhang J, Tran Q, Furnes B, Schlenk D, Cashman JR: Two new polymorphisms of the FMO3 gene in Caucasian and African-American populations: comparative genetic and functional studies. Drug Metab. Dispos. 31, 854-860 (2003).
73. Zschocke J, Mayatepek E: Biochemical and molecular studies in mild flavin monooxygenase 3 deficiency. J. Inher. Metab. Dis. 23, 2000-2378 (2000).
74. 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. 66, 431-438 (1999).
75. Störmer E, Roots I, Brockmöller J: Benzydamine N-oxidation as an index reaction refelcting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity. Br. J. Clin. Pharmacol. 50, 553-561 (2000).
76. Lambert DM, Mamer OA, Akerman BR et al.: In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene. Mol. Genet. Metab. 73, 224-229 (2001).
77. Park C-S, Kang J-H, Chung W-G et al.: Ethnic differences in allelic frequency for two flavin-containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities. Pharmacogenetics 12, 77-80 (2002).
78. Cashman JR, Zhang J, Leushner J, Braun A: Population distribution of human flavin-containing monooxygenase form 3: gene polymorphisms. Drug Metab. Dispos. 29, 1629-1637 (2001).
79. 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. 10, 8357-8362 (2004).
80. Hamman MA, Haehner-Daniels BD, Wrighton SA, Rettie AE, Hall SD: Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases. Biochem. Pharmacol. 60, 7-17 (2000).
81. Cashman JR: Human flavin-containing monooxygenase (form 3): polymorphisms and variations in chemical metabolism. Pharmacogenomics 3, 325-339 (2002).
82. Koukouritaki SB, Poch MT, Cabacungan ET, McCarver DG, Hines RN: Discovery of novel flavin-containing monooxygenase 3 (FMO3) single nucleotide polymorphisms and functional analysis of upstream haplotype variants. Mol. Pharmacol. 68, 383-392 (2005).
83. Kubota M, Nakamoto Y, Nakayama K et al.: A mutation in the flavin-containing monooxygenase 3 gene and its effects on catalytic activity for N-oxidation of trimethylamine in vitro. Drug Metab. Pharmacokin. 17, 207-213 (2002).
84. Stevens JC, Hines RN, Gu C et al.: Developmental expression of the major human hepatic CYP3A enzymes. J. Pharmacol. Exp. Ther. 307, 573-582 (2003).
85. Leeder JS, Gaedigk R, Marcucci KA et al.: Variability of CYP3A7 expression in human fetal liver. J. Pharmacol. Exp. Ther. 314, 626-635 (2005).