Interindividual differences of human flavin-containing monooxygenase 3: genetic polymorphisms and functional variation

Abstract

The human flavin-containing monooxygenase (form 3) (FMO3) participates in the oxygenation of nucleophilic heteroatom-containing drugs, xenobiotics, and endogenous materials. Currently, six forms of the FMO gene are known, but it is FMO3 that is the major form in adult human liver that is likely responsible for the majority of FMO-mediated metabolism. The substrate structural feature requirements for human FMO3 is beginning to become known to a greater extent and a few chemicals extensively metabolized by FMO3 have been reported. Expression of FMO3 is species- and tissue-specific, but unlike human cytochrome p450, mammalian FMO3 does not appear to be inducible. Interindividual variation in FMO3-dependent metabolism of drugs, chemicals, and endogenous material is therefore more likely due to genetic effects and not environmental ones. Examples of such interindividual variation come from the study of very rare mutations of the human FMO3 gene that have been associated with deficient N-oxygenation of dietary trimethylamine. Defective trimethylamine N-oxygenation causes trimethylaminuria or "fish-like odor syndrome". Information on human FMO3 mutations from individuals suffering from the condition of trimethylaminuria has provided knowledge about the underlying molecular mechanism(s) for trimethylaminuria. A number of common variants of human FMO3 have been reported. Diversification of the FMO3 gene may have led to selective advantages and new functions. As more examples of human FMO3-mediated metabolism of drugs or new chemical entities are discovered in the future, it is possible that FMO3 allelic variation may be shown to contribute to interindividual and interethnic variability of FMO-mediated metabolism. Human FMO3 may be another example of an environmental gene that participates in a protective mechanism to help humans ward off potentially toxic exposure of chemicals.