Abstract
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.
Footnotes
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Send reprint requests to: Eileen Treacy, Montreal Children's Hospital, Room A-717, 2300 Tupper Street, Montreal, Quebec, H3H 1P3 Canada. E-mail: mcet{at}musica.mcgill.ca and John Cashman, Human Biomedical Research Institute, 5310 Eastgate Mall, San Diego, CA. E-mail: ledcash{at}aol.com
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This work was financially supported by Grants from the National Institutes of Health (GM-36426 and ES-6973), the Fonds de la Recherche en Santé du Québec (E.P.T.), and the McGill Research and Development Fund (E.P.T.). The work at the Murdoch Institute was funded by an Australian National Health and Medical Research Center Block Grant (S.M.F.).
- Abbreviations used are::
- FMO
- flavin-containing monooxygenase
- TMA
- trimethylamine
- 5-APT
- 10-(5-aminopentyl)-2-(trifluoromethyl)phenothiazine
- 5-DPT
- 10-(N,N-dimethylaminopentyl)-2-(trifluoromethyl)phenothiazine
- MBP
- maltose-binding protein
- Received August 3, 1999.
- Accepted October 3, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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