Correlation between phenotypes of FMO obtained by ranitidine N-oxidation and genotypes of FMO3 in a Korean population

FMO was phenotyped using ranitidine (RA) TV-oxidation and correlated with FMO 3 genotypes in 210 Korean volunteers. Pooled urine samples were collected for 8 hr following oral ingestion of RA (150mg) and urinary molar ratio of (RA)/(RA TV-oxide) was used as a reciprocal index of FMO activity. Distribution of the ratio showed trimodality; 13 (6%) very slow (17.47-27.20), 105 (50%) slow (9.70-15.64) and 92 (44%) fast (5.67-9.58) N-oxidizers. Blood samples were collected from 164 volunteers and genomic DNAs were analyzed for 3 previously found FMO3 mutant alleles (STOP¹⁴⁸, Lys¹⁵⁸ and Gly³⁰⁸) in Korean. Heterozygotic STOP¹⁴⁸ codon was detected only in one volunteer with low FMO activity. The FMO activities of 49 volunteers who had homo- and/or heterozygous mutations in their FMO3 either one or both Lys¹⁵⁸ and Gly³⁰⁸ alleles were lower than those with wild type alleles (n=115) (p<0.0001). Among 13 volunteers with very low FMO activities, 8 were genotyped and 5 were either homoor heterozygous for either one or both of Lys¹⁵⁸ and Gly³⁰⁸ alleles. However, 3 volunteers were homozygous for wild type alleles and indicated that there are still unfound mutant alleles. Combined, these results suggest that the 2 point mutations in FMO3 are involved in FMO polymorphism and may affect pharmacokinetics of drugs metabolized primarily by FMO3.