Phenotypes of flavin-containing monooxygenase activity determined by ranitidine N-oxidation are positively correlated with genotypes of linked FMO3 gene mutations in a Korean population

A non-invasive mine analysis method to determine the in-vivo flavin-contain ing monooxygenase (FMO) activity catalysing N-oxidation of ranitidine (RA) was developed and used to phenotype a Korean population. FMO activity was a ssessed by the molar concentration ratio of RA and RANG in the bulked 8 h u rine. This method was used to determine the FMO phenotypes of 210 Korean vo lunteers (173 men and 37 women, 110 nonsmokers and 100 smokers), Urinary RA /RANO ratio, representing the metabolic ratio and the reciprocal index of F MO activity, ranged from 5.67-27.20 (4.8-fold difference) and was not diffe rent 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 f ashion. Among the 210 Korean subjects, 93 (44.3%) were fast metabolizers, 1 04 (49.5%) were intermediate metabolizers and 13 (6.2%) were slow metaboliz ers. Subsequently, the relationship between the ranitidine N-oxidation phen otypes and FMO3 genotypes, determined by the presence of two previously ide ntified mutant alleles (Glu158Lys: FMO3/Lys(158) and Glu308Gly: FMO3/Gly(30 8) alleles) commonly found in our Korean population was examined. The resul ts showed that subjects who were homozygous and heterozygous for either one or both of the FMO3/Lys(158) and FMO3/Gly(308) mutant alleles had signific antly lower in-vivo FMO activities than those with homozygous wild-type all eles (FMO3/Glu(158) and FMO3/Glu(308)) (P < 0.001, Mann-Whitney U-test). Fu rthermore, the FMO activities of subjects with either FMO3/Lys(158) or FMO3 /Gly(308) mutant alleles were almost identical to those having both FMO3 mu tant alleles (FMO3/Lys(308) and FMO3/Gly(308)), These two mutant alleles lo cated, respectively, at exons 4 and 7 in the FMO3 gene appeared to be stron gly linked by cis-configuration in Koreans, Therefore, we concluded that pr esence of FMO3/Lys(158) and FMO3/Gly(308) mutant alleles in FMO3 gene is re sponsible for the low ranitidine N-oxidation (FMO3 activity) in our Korean population. Pharmacogenetics 10:67-78 (C) 2000 Lippincott Williams & Wilkin s.