Phenotypes of flavin-containing monooxygenase activity determined by ranitidineN-oxidation are positively correlated with genotypes of linkedFMO3gene mutations in a Korean population
作者:
Ju-Hee Kang,
Woon-Gye Chung,
Kyung-Hoon Lee,
Chang-Shin Park,
Ju-Seop Kang,
In-Chul Shin,
Hyung-Keun Roh,
Mi-Sook Dong,
Hyun-Moon Baek,
Young-Nam Cha,
期刊:
Pharmacogenetics
(OVID Available online 2000)
卷期:
Volume 10,
issue 1
页码: 67-78
ISSN:0960-314X
年代: 2000
出版商: OVID
关键词: FMO3;ranitidine;phenotype;genotype;linkage;Korean
数据来源: OVID
摘要:
A non-invasive urine analysis method to determine the in-vivo flavin-containing monooxygenase (FMO) activity catalysingN-oxidation of ranitidine (RA) was developed and used to phenotype a Korean population. FMO activity was assessed by the molar concentration ratio of RA and RANO in the bulked 8 h urine. This method was used to determine the FMO phenotypes of 210 Korean volunteers (173 men and 37 women, 110 nonsmokers and 100 smokers). Urinary RA/RANO ratio, representing the metabolic ratio and the reciprocal index of FMO activity, ranged from 5.67–27.20 (4.8-fold difference) and was not different between men and women (P = 0.76) or between smokers and nonsmokers (P = 0.50). The frequencies of RA/RANO ratios were distributed in a trimodal fashion. Among the 210 Korean subjects, 93 (44.3%) were fast metabolizers, 104 (49.5%) were intermediate metabolizers and 13 (6.2%) were slow metabolizers. Subsequently, the relationship between the ranitidineN-oxidation phenotypes andFMO3genotypes, determined by the presence of two previously identified mutant alleles (Glu158Lys: FMO3/Lys158and Glu308Gly: FMO3/Gly308alleles) commonly found in our Korean population was examined. The results showed that subjects who were homozygous and heterozygous for either one or both of the FMO3/Lys158and FMO3/Gly308mutant alleles had significantly lower in-vivo FMO activities than those with homozygous wild-type alleles (FMO3/Glu158and FMO3/Glu308) (P < 0.001, Mann–WhitneyU-test). Furthermore, the FMO activities of subjects with either FMO3/Lys158or FMO3/Gly308mutant alleles were almost identical to those having both FMO3 mutant alleles (FMO3/Lys158and FMO3/Gly308). These two mutant alleles located, respectively, at exons 4 and 7 in theFMO3gene appeared to be strongly linked bycis-configuration in Koreans. Therefore, we concluded that presence of FMO3/Lys158and FMO3/Gly308mutant alleles inFMO3gene is responsible for the low ranitidineN-oxidation (FMO3 activity) in our Korean population.
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