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ToxSci Advance Access originally published online on February 19, 2004
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Toxicological Sciences 78, 196-203 (2004)
Toxicological Sciences vol. 78 no. 2 © Society of Toxicology; all rights reserved.

Evaluation of Xenobiotic N- and S-Oxidation by Variant Flavin-Containing Monooxygenase 1 (FMO1) Enzymes

Bjarte Furnes1 and Daniel Schlenk

Environmental Toxicology Program, University of California, Riverside, California 92521

Received November 25, 2003; accepted January 20, 2004

The flavin-containing monooxygenase gene family (FMO1–6) in humans encodes five functional isoforms that catalyze the monooxygenation of numerous N-, P- and S-containing drugs and toxicants. A previous single nucleotide polymorphism (SNP) analysis of FMO1 in African-Americans identified seven novel SNPs. To determine the functional relevance of the coding FMO1 variants (H97Q, I303V, I303T, R502X), they were heterologously expressed using a baculovirus system. Catalytic efficiency and stereoselectivity of N- and S-oxygenation was determined in the FMO1 variants using several substrates. The I303V variant showed catalytic constants equal to wild-type FMO1 for methimazole and methyl p-tolyl sulfide. Catalytic efficiency (Vmax/Km) of methyl p-tolyl sulfide oxidation by R502X was unaltered. In contrast, methimazole oxidation by R502X was not detected. Both H97Q and I303T had elevated catalytic efficiency with regards to methyl p-tolyl sulfide (162% and 212%, respectively), but slightly reduced efficiency with regards to methimazole (81% and 78%). All the variants demonstrated the same stereoselectivity for methyl p-tolyl sulfide oxidation as wild-type FMO1. FMO1 also metabolized the commonly used insecticide fenthion to its (+)-sulfoxide, with relatively high catalytic efficiency. FMO3 metabolized fenthion to its sulfoxide at a lower catalytic efficiency than FMO1 (27%) and with less stereoselectivity (74% (+)-sulfoxide). Racemic fenthion sulfoxide was a weaker inhibitor of acetylcholinesterase than its parent compound (IC50 0.26 and 0.015 mM, respectively). The (+)- and (-)-sulfoxides were equally potent inhibitors of acetylcholinesterase. These data indicate that all the currently known FMO1 variants are catalytically active, but alterations in kinetic parameters were observed.

Key Words: flavin-containing monooxygenase; fenthion; thiourea; methimazole; African-American; polymorphisms.


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 Drug Metab. Dispos.Home page
B. Furnes and D. Schlenk
EXTRAHEPATIC METABOLISM OF CARBAMATE AND ORGANOPHOSPHATE THIOETHER COMPOUNDS BY THE FLAVIN-CONTAINING MONOOXYGENASE AND CYTOCHROME P450 SYSTEMS
Drug Metab. Dispos., February 1, 2005; 33(2): 214 - 218.
[Abstract] [Full Text] [PDF]


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