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KMID : 0391020000080010044
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Journal of Korean Society for Clinical Pharmacology and Therapeutics
2000 Volume.8 No. 1 p.44 ~ p.59
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Correlation Between FMO3 Genotypes and FMO Activity measured by Using Trimethylamine N-Oxidation and Ranitidine N-Oxidation
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Sung Song-Ki
Cha Young-Nam
Shin Sang-Goo
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Abstract
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Background: While trimethylamine (TMA) has been available for a non-invasive determination of flavin-containing monooxygenase 3 (FMO3) activity in man, it is contained in many foods and thus insensitive. We recently developed a non-invasive ranitidine N-oxidation test to determine the in vivo FMO activity. In this study, we compared the sensitivities of these two FMO phenotyping methods in reference to the FMO3 mutant genotypes by examining the functional effects of FMO3E158K and E308G mutations on the rates of in vivo
TMA N-oxidation and ranitidine N-oxidation by cross-over design.
Methods: In 36 Korean healthy volunteers who were genotyped for the presence of K158 and G308 mutations in their FMO3 gene, FMO activities were determined by using ranitidine N-oxidation and TMA N-oxidation. Ratios of TMA N-oxide (TMAO) over total TMA(TTMA) in 24-hour urine and of ranitidine N-oxide versus ranitidine in 8-hour urine after an oral ingestion of 150mg ranitidine were determined.
Results: Ratios of TMAO/TTMA obtained in 13 subjects with home- or heterozygous FMO3K158 mutant alleles were not different from those of 23 subjects with wild type FMO3 E158 allele, and also, the ratios in 12 subjects with homo- or heterozygous FMO3 G308 mutant alleles were not different from those of 24 subjects with wild type FMO3 E308 allele. However, the ranitidine N-oxide/ranitidine ratios of 13 subjects with homo- or heterozygous FMO3 K158 mutant alleles were significantly lower than those of the 23 subjects with FMO3 E158 wild type alleles, and also, the ratios of 12 subjects with FMO3 G308 mutant alleles were lower than those of the 23 subjects with wild type FMO3 E308 alleles.
Conclusion: FMO activities determined by ranitidine N-oxidation, but not by TMA N-oxidation, were sensitively correlated with the common FMO3 E158K and E308G mutant genotypes in our Korean subjects.
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KEYWORD
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FMO, FMO3 genotype, Polymorphism, TMA N-oxidation, Ranitidine N-oxidation,
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