Population-specific polymorphisms of the human FMO3 gene: Significance fordetoxication

Flavin-containing monooxygenase form 3 (FMO3) is one of the major enzyme sy stems that protect humans from the potentially toxic properties of drugs an d chemicals. FMO3 converts nucleophilic heteroatom-containing chemicals and endogenous materials to polar metabolites, which facilitates their elimina tion. For example, the tertiary amine trimethylamine is N-oxygenated by hum an FMO3 to trimethylamine N-oxide, and trimethylamine N-oxide is excreted i n a detoxication and deoderation process. In normal humans, virtually all t rimethylamine is metabolized to trimethylamine N-oxide. In a few humans, tr imethylamine is not efficiently metabolized to trimethylamine N-oxide, and those individuals suffer from trimethylaminuria, or fishlike odor syndrome. Previously, we identified mutations of the FMO3 gene that cause trimethyla minuria. We now report two prevalent polymorphisms of this gene (K158E and V257M) that modulate the activity of human FMO3. These polymorphisms are wi dely distributed in Canadian and Australian white populations. In vitro ana lysis of wild-type and variant human FMO3 proteins expressed from the cDNA for the two naturally occurring polymorphisms showed differences in substra te affinities for nitrogen-containing substrates. Thus, for polymorphic for ms of human FMO3, lower k(cat)/K-m values for N-oxygenation of 10-(N,N-dime thylaminopentyl)-2-(trifluoromethyl) phenothiazine, trimethylamine, and tyr amine were observed. On the basis of in vitro kinetic parameters, human FMO 1 does not significantly contribute to human metabolism of trimethylamine o r tyramine. The results imply that prevalent polymorphisms of the human FMO 3 gene may contribute to low penetrance predispositions to diseases associa ted with adverse environmental exposures to heteroatom-containing chemicals , drugs, and endogenous amines.