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

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.

SUBMITTER: Nagashima S

PROVIDER: S-EPMC4755719 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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

Nagashima Satomi S Shimizu Makiko M Yano Hiroshi H Murayama Norie N Kumai Toshio T Kobayashi Shinichi S Guengerich F Peter FP Yamazaki Hiroshi H

Drug metabolism and pharmacokinetics 20090101 3

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 ...[more]

PMID: 19571433

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Project description:Busulphan (Bu) is an alkylating agent used in the conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Bu is extensively metabolized in the liver via conjugations with glutathione to form the intermediate metabolite (sulfonium ion) which subsequently is degraded to tetrahydrothiophene (THT). THT was reported to be oxidized forming THT-1-oxide that is further oxidized to sulfolane and finally 3-hydroxysulfolane. However, the underlying mechanisms for the formation of these metabolites remain poorly understood. In the present study, we performed in vitro and in vivo investigations to elucidate the involvement of flavin-containing monooxygenase-3 (FMO3) and cytochrome P450 enzymes (CYPs) in Bu metabolic pathway. Rapid clearance of THT was observed when incubated with human liver microsomes. Furthermore, among different recombinant microsomal enzymes, the highest intrinsic clearance for THT was obtained via FMO3 followed by several CYPs including 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4. In Bu- or THT-treated mice, inhibition of FMO3 by phenylthiourea significantly suppressed the clearance of both Bu and THT. Moreover, the simultaneous administration of a high dose of THT (200μmol/kg) to Bu-treated mice reduced the clearance of Bu. Consistently, in patients undergoing HSCT, repeated administration of Bu resulted in a significant up-regulation of FMO3 and glutathione-S-transfrase -1 (GSTA1) genes. Finally, in a Bu-treated patient, additional treatment with voriconazole (an antimycotic drug known as an FMO3-substrate) significantly altered the Bu clearance. In conclusion, we demonstrate for the first time that FMO3 along with CYPs contribute a major part in busulphan metabolic pathway and certainly can affect its kinetics. The present results have high clinical impact. Furthermore, these findings might be important for reducing the treatment-related toxicity of Bu, through avoiding interaction with other concomitant used drugs during conditioning and hence improving the clinical outcomes of HSCT.

Dataset Information

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

Publications

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

Similar Datasets

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