Inter-individual variation in flavin-containing monooxygenase 3 in livers from Japanese: correlation with hepatic transcription factors

Drug Metab Pharmacokinet. 2009;24(3):218-25. doi: 10.2133/dmpk.24.218.

Abstract

Human flavin-containing monooxygenase 3 (FMO3)-mediated microsomal oxygenation activity, levels of FMO3 protein and FMO3 mRNA and modifications were investigated in Japanese livers genotyped for the FMO3 gene. Significant correlations were observed for benzydamine N-oxygenation or methyl p-tolyl sulfide S-oxygenation activity (in the range of approximately 20- to approximately 40-fold) and FMO3 levels determined immunochemically in liver microsomes (r(2)=0.73-0.75, p<0.0001, n=16). Preincubation with the reducing agent ascorbate revealed that FMO3 activity in some liver samples is suppressed. Microsomal FMO3 protein content (approximately 40-fold) was correlated with FMO3 mRNA levels (r(2)=0.55, p=0.0010, n=16), but FMO3 haplotypes did not affect FMO3 mRNA expression (approximately 100-fold) under the conditions used. FMO3 mRNA levels were multivariately correlated with trans-acting factors, i.e. hepatic nuclear factor 4 (HNF-4) mRNA and nuclear factor Y box-binding protein (NF-Y) mRNA (r(2)=0.31, p=0.0017, n=37). These results suggest that considerable individual differences in FMO3 levels may exist in Japanese livers. The liver-enriched transcription factor HNF-4 appears to be a determinant of FMO3 expression in livers, as well as the ubiquitous factor NF-Y.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asian People / genetics
  • Benzodiazepines / metabolism
  • Benzydamine / metabolism
  • CCAAT-Binding Factor / metabolism
  • Genetic Variation
  • Hepatocyte Nuclear Factor 4 / physiology
  • Humans
  • Hydrogen-Ion Concentration
  • Microsomes, Liver / enzymology*
  • Olanzapine
  • Osmolar Concentration
  • Oxygenases / genetics*
  • RNA, Messenger / metabolism
  • S-Nitroso-N-Acetylpenicillamine / pharmacology
  • Sulfides / metabolism

Substances

  • CCAAT-Binding Factor
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • NFYA protein, human
  • RNA, Messenger
  • Sulfides
  • methyl 4-tolylsulfide
  • Benzodiazepines
  • Benzydamine
  • S-Nitroso-N-Acetylpenicillamine
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • Olanzapine