Dependence of microsomal methoxyflurane O-demethylation on cytochrome P-450 reductase and the stoichiometry of fluoride ion and formaldehyde release.
In order to characterize further the in vitro liver microsomal O-demethylation and defluorination of the volatile anesthetic methoxyflurane, and obtain additional information regarding the participation of cytochrome P-450 in the oxidation, the stoichiometry of the reaction was determined and the effect of antibody to cytochrome P-450 reductase on this unique biotransformation was examined. Liver microsomes were isolated from rabbits and rats in which enzyme induction had previously been produced by phenobarbital. The O-demethylation of methoxyflurane by phenobarbital-induced microsomes results in the production of 1 mol of formaldehyde for every 2 mol of fluoride ion produced. Dichloroacetic acid is also a product of methoxyflurane O-demethylation. Antibody to cytochrome P-450 reductase inhibits by 85% the amount of fluoride ion produced by the microsomal metabolism of methoxyflurane. Thus critical indirect supportive data are contributed to the hypothesis that at least one, but perhaps more, cytochrome P-450 is indeed responsible for methoxyflurane O-demethylation and defluorination.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003579:Cytochrome Reductases / Q000378:metabolism*; D003640:Dealkylation; D005459:Fluorides / Q000378:metabolism; D005557:Formaldehyde / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008733:Methoxyflurane / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D008956:Models, Chemical; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344
D005557:Formaldehyde; D008733:Methoxyflurane; D003577:Cytochrome P-450 Enzyme System; D003579:Cytochrome Reductases; D005459:Fluorides