Phenotypes of flavin-containing monooxygenase activity determined by ranitidine N-oxidation are positively correlated with genotypes of linked FM03 gene mutations in a Korean population.
A non-invasive urine analysis method to determine the in-vivo flavin-containing mono-oxygenase (FMO) activity catalysing N-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 ranitidine N-oxidation phenotypes and FMO3 genotypes, determined by the presence of two previously identified mutant alleles (Glu158Lys: FMO3/Lys158 and Glu308Gly: FMO3/Gly308 alleles) 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/Lys158 and FMO3/Gly308 mutant alleles had significantly lower in-vivo FMO activities than those with homozygous wild-type alleles (FMO3/Glu158 and FMO3/Glu308) (P < 0.001, Mann-Whitney U-test). Furthermore, the FMO activities of subjects with either FMO3/Lys158 or FMO3/Gly308 mutant alleles were almost identical to those having both FMO3 mutant alleles (FMO3/Lys158 and FMO3/Gly308). These two mutant alleles located, respectively, at exons 4 and 7 in the FMO3 gene appeared to be strongly linked by cis-configuration in Koreans. Therefore, we concluded that presence of FMO3/Lys158 and FMO3/Gly308 mutant alleles in FMO3 gene is responsible for the low ranitidine N-oxidation (FMO3 activity) in our Korean population.
Kang
J H
JH
Department of Pharmacology and Toxicology, College of Medicine, Inha University, Inchon, Korea.
Chung
W G
WG
Lee
K H
KH
Park
C S
CS
Kang
J S
JS
Shin
I C
IC
Roh
H K
HK
Dong
M S
MS
Baek
H M
HM
Cha
Y N
YN
D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007723:Korea; D008297:Male; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000097:blood / Q000235:genetics* / Q000652:urine*; D010641:Phenotype; D011899:Ranitidine / Q000031:analogs & derivatives / Q000652:urine*; D012016:Reference Values; D012737:Sex Factors; D012907:Smoking / Q000235:genetics / Q000378:metabolism
C045907:ranitidine-S-oxide; D011899:Ranitidine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C038169:ranitidine N-oxide