title: Stereoselective sulfoxidation of the pesticide methiocarb by flavin-containing monooxygenase and cytochrome P450-dependent monooxygenases of rat liver microsomes. Anticholinesterase activity of the two sulfoxide enantiomers.
abstract: Evidence based on thermal lability and enzyme inhibition data suggests that the sulfoxidation of methiocarb (an N-methylcarbamate insecticide) by rat liver microsomes is catalyzed by flavin-containing monooxygenase(s) (FMO) and by cytochrome(s) P450 (P450). In control rats, the relative proportion is ca. 50% P450:50% FMO. Stereoselective formation of methiocarb sulfoxide from the corresponding sulfide has also been examined to compare the enantioselectivity of the two different enzyme systems. Only the FMO-dependent sulfoxidation presents a high stereoselectivity with an enantiomeric excess of 88% in favor of the (A)-enantiomer. Pretreatment of rats with different P450 inducers such as phenobarbital, 3-methylcholanthrene, dexamethasone, and pyrazole did not affect, or decreased, the rate of methiocarb sulfoxidation. Stereoselectivity of the reaction was modified, mainly because of changes in the relative involvement of FMO and P450 in sulfoxidase activity in pretreated animals. The acetylcholinesterase inhibition properties of methiocarb and its main metabolites were also investigated. Racemic methiocarb sulfoxide was slightly less inhibitory (Ki = 0.216 microM-1.min-1) than methiocarb, but a 10-fold difference was observed between the bimolecular rate constants found for the two sulfoxides produced (0.054 and 0.502 microM-1.min-1 for the (A) and (B) enantiomers, respectively).
authors.affiliation: Unité de Toxicologie Métabolique et d'Ecotoxicologie INRA-ENVL, Ecole Nationale Vétérinaire de Lyon, Marcy l'Etoile, France.
authors.forename: T
authors.initials: T
authors.lastname: Buronfosse
authors.forename: P
authors.initials: P
authors.lastname: Moroni
authors.forename: E
authors.initials: E
authors.lastname: Benoît
authors.forename: J L
authors.initials: JL
authors.lastname: Rivière
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D007306:Insecticides / Q000378:metabolism*; D008297:Male; D008714:Methiocarb / Q000031:analogs & derivatives / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D008714:Methiocarb; C097911:methiocarb sulfoxide