PT  - JOURNAL ARTICLE
AU  - Cashman, John R.
AU  - Akerman, Beverly R.
AU  - Forrest, Susan M.
AU  - Treacy, Eileen P.
TI  - Population-Specific Polymorphisms of the Human<em>FMO3</em> Gene: Significance for Detoxication
DP  - 2000 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 169--173
VI  - 28
IP  - 2
4099  - http://dmd.aspetjournals.org/content/28/2/169.short
4100  - http://dmd.aspetjournals.org/content/28/2/169.full
SO  - Drug Metab Dispos2000 Feb 01; 28
AB  - Flavin-containing monooxygenase form 3 (FMO3) is one of the major enzyme systems that protect humans from the potentially toxic properties of drugs and chemicals. FMO3 converts nucleophilic heteroatom-containing chemicals and endogenous materials to polar metabolites, which facilitates their elimination. For example, the tertiary amine trimethylamine is N-oxygenated by human FMO3 to trimethylamine N-oxide, and trimethylamineN-oxide is excreted in a detoxication and deoderation process. In normal humans, virtually all trimethylamine is metabolized to trimethylamine N-oxide. In a few humans, trimethylamine is not efficiently metabolized to trimethylamineN-oxide, and those individuals suffer from trimethylaminuria, or fishlike odor syndrome. Previously, we identified mutations of the FMO3 gene that cause trimethylaminuria. We now report two prevalent polymorphisms of this gene (K158E and V257M) that modulate the activity of human FMO3. These polymorphisms are widely distributed in Canadian and Australian white populations. In vitro analysis of wild-type and variant human FMO3 proteins expressed from the cDNA for the two naturally occurring polymorphisms showed differences in substrate affinities for nitrogen-containing substrates. Thus, for polymorphic forms of human FMO3, lowerkcat/Km values for N-oxygenation of 10-(N,N-dimethylaminopentyl)-2-(trifluoromethyl) phenothiazine, trimethylamine, and tyramine were observed. On the basis of in vitro kinetic parameters, human FMO1 does not significantly contribute to human metabolism of trimethylamine or tyramine. The results imply that prevalent polymorphisms of the humanFMO3 gene may contribute to low penetrance predispositions to diseases associated with adverse environmental exposures to heteroatom-containing chemicals, drugs, and endogenous amines. The American Society for Pharmacology and Experimental Therapeutics