Inter-individual variation in flavin-containing monooxygenase 3 in livers from Japanese: correlation with hepatic transcription factors.
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.
Nagashima
Satomi
S
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan.
Shimizu
Makiko
M
Yano
Hiroshi
H
Murayama
Norie
N
Kumai
Toshio
T
Kobayashi
Shinichi
S
Guengerich
F Peter
FP
Yamazaki
Hiroshi
H
D044466:Asian People / Q000235:genetics; D001569:Benzodiazepines / Q000378:metabolism; D001591:Benzydamine / Q000378:metabolism; D023081:CCAAT-Binding Factor / Q000378:metabolism; D014644:Genetic Variation; D051557:Hepatocyte Nuclear Factor 4 / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008862:Microsomes, Liver / Q000201:enzymology*; D000077152:Olanzapine; D009994:Osmolar Concentration; D010105:Oxygenases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013440:Sulfides / Q000378:metabolism
D023081:CCAAT-Binding Factor; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C492061:NFYA protein, human; D012333:RNA, Messenger; D013440:Sulfides; C544071:methyl 4-tolylsulfide; D001569:Benzodiazepines; D001591:Benzydamine; D026423:S-Nitroso-N-Acetylpenicillamine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D000077152:Olanzapine