The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지

Alteration of Substrate Specificity by Common Variants, E158K/E308G and V257M, in Human Hepatic Drug-metabolizing Enzyme, Flavin-containing Monooxygenase 3

  • Lee, Jung-Kyu (Department of Pharmacology, College of Medicine, Inha University) ;
  • Kang, Ju-Hee (Department of Pharmacology, College of Medicine, Inha University) ;
  • Cha, Young-Nam (Department of Pharmacology, College of Medicine, Inha University) ;
  • Chung, Woon-Gye (Department of Pharmacology, College of Medicine, Inha University,Medicinal Toxicology Research Center, Inha University) ;
  • Park, Chang-Shin (Department of Pharmacology, College of Medicine, Inha University,Medicinal Toxicology Research Center, Inha University)
  • Published : 2003.06.21
Download PDF
⟨ Previous Next ⟩

Abstract

Our earlier studies found a significant correlation between the activities of ranitidine N-oxidation catalyzed by hepatic flavin-containing monooxygenase (FMO) and the presence of mutations in exon 4 (E158K) and exon 7 (E308G) of the FMO3 gene in Korean volunteers. However, caffeine N-1 demethylation (which is also partially catalyzed by FMO) was not significantly correlated with these FMO3 mutations. In this study, we examined another common mutation (V257M) in exon 6 of FMO3 gene. The V257M variant, which is caused by a point mutation (G769A), was commonly observed (13.21% allele frequency) in our subjects (n=159). This point mutation causes a substitution of $Val^{257}$ to $Met^{257}$, with transformation of the secondary structure. The presence of this mutant allele correlated significantly with a reduction in caffeine N-1-demethylating activity, but was not correlated with the activity of N-oxidation of ranitidine. In a family study, the low FMO activity observed in a person heterozygous for a nonsense mutation in exon 4 (G148X) and heterozygous for missense mutation in exon 6 (V257M) of FMO3 was attributed to the mutations. Our results suggest that various point mutations in the coding regions of FMO3 may influence FMO3 activity according to the probe substrates of varying chemical structure that correlate with each mutation on the FMO3 gene.

Keywords

References

  1. Cashman JR. Structural and catalytic properties of the mammalian flavin-containing monooxygenase. Chem Res Toxicol 8: 165- 181, 1995 https://doi.org/10.1021/tx00044a001
  2. Cashman JR. Flavin monooxygenases. In: Ioannides C ed, Enzyme systems that metabolize drugs and other xenobiotics, John Wiley & Sons, London, UK, pp 67-93, 2002a
  3. Cashman JR. Human flavincontaining monooxygenase (form 3): polymorphisms and variations in chemical metabolism. Pharmacogenomics 3: 325-339, 2002b https://doi.org/10.1517/14622416.3.3.325
  4. Chung WG, Cha YN. Oxidation of caffeine to theobromine and theophylline is catalyzed primarily by flavin-containing monooxygenase in liver microsomes. Biochem Biophys Res Commun 235: 685-688, 1997 https://doi.org/10.1006/bbrc.1997.6866
  5. Chung WG, Roh KH, Kim HM, Cha YN. Involvement of CYP3A1, 2B1, and 2E1 in C-8 hydroxylation and CYP1A2 and flavincontaining monooxygenase in N-demethylation of caffeine: identified by using inducer treated rat liver microsomes that are characterized with testosterone metabolic patterns. Chem Biol Interact 113: 1-14, 1998 https://doi.org/10.1016/S0009-2797(97)00109-9
  6. Chung WG, Kang JH, Roh HK, Lee KH, Park CS, Cha YN. Assessment of flavin-containing monooxygenase (FMO) activity by determining urinary ratio of theobromine and caffeine in a Korean population after drinking a cup of coffee. Korean J Physiol Pharmacol 3: 207-213, 1999
  7. Chung WG, Kang JH, Park CS, Cho MH, Cha YN. Effect of age and smoking on in vivo CYP1A2, flavin-containing monooxygenase, and xanthine oxidase activities in Koreans: determination by caffeine metabolism. Clin Pharmacol Ther 67: 258-266, 2000 https://doi.org/10.1067/mcp.2000.104617
  8. 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 flavincontaining monooxygenase family of man, FMO1, FMO3 and FMO4. Eur J Biochem 235: 683-689, 1996 https://doi.org/10.1111/j.1432-1033.1996.00683.x
  9. Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR. Missense mutation in flavin-containing monooxygenase 3 gene, FMO3, underlies fish-odor syndrome. Nature Genetics 17: 491- 494, 1997a https://doi.org/10.1038/ng1297-491
  10. Dolphin CT, Riley JH, Smith RL, Shephard EA, Phillips IR. Structural organization of the human flavin-containing monooxygenase gene (FMO3), the favored candidate for fish-odor syndrome, determined directly from genomic DNA. Genomics 46:260-267, 1997b https://doi.org/10.1006/geno.1997.5031
  11. Kang JH, Chung WG, Lee KH, Park CS, Kang JS, Shin IC, Roh HK, Dong MS, Baek HM, Cha YN. 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 10: 67-78, 2000 https://doi.org/10.1097/00008571-200002000-00009
  12. Lomri N, Gu Q, Cashman JR. Molecular cloning of the flavincontaining monooxygenase (form II) cDNA from adult human liver. Proc Natl Acad Sci 89: 685-1689, 1992
  13. Lomri N, Yang ZC, Cashman JR. Regio- and stereoselective oxygenations by adult human liver flavin-containing monooxygenase 3. Comparison with forms 1 and 2. Chem Res Toxicol 6: 800-807, 1993 https://doi.org/10.1021/tx00036a008
  14. Nagata T, Williams DE, Ziegler DM. Substrate specificities of rabbit lung and porcine liver flavin-containing monooxygenases: Differences due to substrate specificity. Chem Res Toxicol 3: 372- 376, 1990 https://doi.org/10.1021/tx00016a016
  15. Oliver CF, Modi S, Sutcliffe MJ, Primrose WU, Lian LY, Robert GC. A single mutation in cytochrome P450 BM3 changes substrate orientation in a catalytic intermediate and the regiospecificity of hydroxylation. Biochemistry 36: 1567-1572, 1997 https://doi.org/10.1021/bi962826c
  16. Oscarson M, Hidestrand M, Johansson I, Ingelman-Sundberg M. A combination of mutations in the CYP2D6*17 (CYP2D6Z) allele causes alteration in enzyme function. Mol Pharmacol 52: 1034- 1040, 1997 https://doi.org/10.1124/mol.52.6.1034
  17. Overby LH, Carver GC, Philpot RM. Quantitation and kinetic properties of hepatic microsomal and recombinant flavincontaining monooxygenases 3 and 5 from humans. Chem Biol Interact 106:29-45, 1997 https://doi.org/10.1016/S0009-2797(97)00055-0
  18. Park CS, Chung WG, Kang JH, Roh HK, Lee KH, Cha YN. Phenotyping of flavin-containing monooxygenase using caffeine metabolism and genotyping of FMO3 gene in a Korean population. Pharmacogenetics 9: 155-164, 1999
  19. Treacy EP, Akerman BR, Chow LML, Youil R, Bibeau C, Lin J, Bruce AG, Knight M, Danks DM, Cashman JR, Forrest SM. Mutations of the flavin-containing monooxygenase gene (FMO3) cuase trimethylaminuria, a defect in detoxication. Hum Mol Genet 7: 839-845, 1998 https://doi.org/10.1093/hmg/7.5.839
  20. Treacy EP, Akerman BR, Chow LML, Youil R, Bibeau C, Lin J, Bruce AG, Knight M, Danks DM, Cashman JR, Forrest SM. Mutations of the flavin-containing monooxygenase gene (FMO3) cuase trimethylaminuria, a defect in detoxication. Hum Mol Genet 7: 839-845, 1998 https://doi.org/10.1093/hmg/7.5.839
  21. Ziegler DM. Flavin-containing monooxygenases: catalytic mechanism and substrate specificities. Drug Metab Rev 19: 1-32, 1988 https://doi.org/10.3109/03602538809049617
  22. Ziegler DM. Flavin-containing monooxygenase: enzyme adapted for multisubstrate specificity. Trends Pharmacol Sci 11: 321-324, 1990 https://doi.org/10.1016/0165-6147(90)90235-Z