Human flavin-containing monooxygenase (form 3): polymorphisms and variations in chemical metabolism

Abstract

The human flavin-containing monooxygenases catalyze the oxygenation of nucleophilic heteroatom-containing drugs, xenobiotics and endogenous materials. Evidence for six forms of the FMO gene exist but it is FMO form 3 (FMO3) that is the prominent form in adult human liver that is likely to be associated with the bulk of FMO-mediated metabolism. An understanding of the substrate specificity of human FMO3 is beginning to emerge and several examples of drugs and chemicals extensively metabolized by FMO3 have been reported. Expression of FMO3 is species- and tissue-specific, but unlike human cytochrome P450 (CYP450), mammalian FMO3 does not appear to be inducible. Interindividual variation in FMO3-dependent metabolism of drugs, chemicals and endogenous materials is therefore more likely to be due to genetic and not environmental effects. Certain mutations of the human FMO3 gene have been associated with abnormal N-oxygenation of trimethylamine. Deficient N-oxygenation of trimethylamine results in a condition called trimethylaminuria. Some treatment strategies for this inborn error of metabolism are discussed. Other common variants of the FMO3 gene including E158K, V257M and E308G have been observed. It is possible that allelic variation of human FMO3 causes abnormal metabolism of chemicals and has clinical implications for human drug metabolism, but this is an understudied area. Human FMO3 allelic variation may eventually be shown to contribute to interindividual and interethnic variability in FMO3-mediated metabolism. Human FMO3 may be another example of an environmental gene that participates in a protective mechanism to help shield humans from potentially toxic exposure to chemicals. Heterogeneity in the relative frequencies of single and multiple site alleles, haplotypes and genotypes of the human FMO3 amongst various ethnic groups suggests population differences.