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

Nagashima S, Shimizu M, Yano H, Murayama N, Kumai T, Kobayashi S, Guengerich FP, Yamazaki H
Drug Metab Pharmacokinet. 2009 24 (3): 218-25

PMID: 19571433 · PMCID: PMC4755719 · DOI:10.2133/dmpk.24.218

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.

MeSH Terms (15)

Asian Continental Ancestry Group Benzodiazepines Benzydamine CCAAT-Binding Factor Genetic Variation Hepatocyte Nuclear Factor 4 Humans Hydrogen-Ion Concentration Microsomes, Liver Olanzapine Osmolar Concentration Oxygenases RNA, Messenger S-Nitroso-N-Acetylpenicillamine Sulfides

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