Alteration of Substrate Specificity by Common Variants, E158K/E308G and V257M, in Human Hepatic Drug-metabolizing Enzyme, Flavin-containing Monooxygenase 3.
- Author:
Jung Kyu LEE
1
;
Ju Hee KANG
;
Young Nam CHA
;
Woon Gye CHUNG
;
Chang Shin PARK
Author Information
1. Department of Pharmacology, College of Medicine, Inha University, Incheon 402-751, Korea. parkshin@inha.ac.kr
- Publication Type:Original Article
- Keywords:
Flavin-containing monooxygenase;
Polymorphism;
Caffeine;
Ranitidine;
Substrate specificity;
Phenotype;
Genotype;
Human
- MeSH:
Alleles;
Caffeine;
Clinical Coding;
Codon, Nonsense;
Exons;
Genotype;
Humans*;
Mutation, Missense;
Phenotype;
Point Mutation;
Ranitidine;
Substrate Specificity*;
Volunteers
- From:The Korean Journal of Physiology and Pharmacology
2003;7(3):157-162
- CountryRepublic of Korea
- Language:English
-
Abstract:
Our earlier studies found a significant correlation between the activities of ranitidine N-oxidation catalyzed by hepatic flavin-containing monooxygenase (FMO) and the presence of mutations in exon 4 (E158K) and exon 7 (E308G) of the FMO3 gene in Korean volunteers. However, caffeine N-1 demethylation (which is also partially catalyzed by FMO) was not significantly correlated with these FMO3 mutations. In this study, we examined another common mutation (V257M) in exon 6 of FMO3 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 Val257 to Met257, with transformation of the secondary structure. The presence of this mutant allele correlated significantly with a reduction in caffeine N-1-demethylating activity, but was not correlated with the activity of N-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 FMO3 was attributed to the mutations. Our results suggest that various point mutations in the coding regions of FMO3 may influence FMO3 activity according to the probe substrates of varying chemical structure that correlate with each mutation on the FMO3 gene.
