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KCI등재 학술저널

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

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

Our earlier studies found a significant correlation between the activities of ranitidine <I>N</I>-oxidation catalyzed by hepatic flavin-containing monooxygenase (FMO) and the presence of mutations in exon 4 (E158K) and exon 7 (E308G) of the <I>FMO3</I> gene in Korean volunteers. However, caffeine <I>N</I>-1 deme</I>thylation (which is also partially catalyzed by FMO) was not significantly correlated with these <I>FMO3</I> mutations. In this study, we examined another common mutation (V257M) in exon 6 of <I>FMO3 </I>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<SUP>257</SUP> to Met<SUP>257</SUP>, with transformation of the secondary structure. The presence of this mutant allele correlated significantly with a reduction in caffeine <I>N-</I>1-demethylating activity, but was not correlated with the activity of <I>N</I>-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 <I>FMO3 </I>was attributed to the mutations. Our results suggest that various point mutations in the coding regions of <I>FMO3</I> may influence FMO3 activity according to the probe substrates of varying chemical structure that correlate with each mutation on the <I>FMO3</I> gene.

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