Intramolecular deuterium isotope effect and enantiotopic differentiation in oxidative demethylation of chiral [monomethyl-d3]methoxychlor in rat liver microsomes.
Intramolecular deuterium kinetic isotope effects on the O-demethylation of methoxychlor [2,2-bis-(4-methoxyphenyl)-1,1,1-trichloroethane] were measured in liver microsomes taken from rats treated with phenobarbital or beta-naphthoflavone and from untreated rats. The substrates were (R)-, (S)- and racemic [monomethyl-d3]methoxychlor, and the ratio of [d3]- to [d0]-mono-O-demethylated metabolites was measured by GC-MS selected-ion monitoring. The magnitude of the observed ratio of [d3]- to [d0]-metabolites in each microsomal preparation was largest on the reaction of the (S)-substrate, followed by racemic substrate, and then (R). Each value is a composite of the intramolecular kinetic isotope effect and enantiotopic differentiation during the reaction. Each intramolecular isotope effect value estimated from these values was smaller than the reported intrinsic value. A relatively slow intramolecular interchange of two methoxyl groups in the methoxychlor molecule in the enzyme-substrate complex was indicated during the reaction. There also was evidence of high enantiotopic differentiation.
Ichinose
R
R
Radioisotope Research Center, Kyoto University, Japan.
Kurihara
N
N
D000818:Animals; D003640:Dealkylation; D003903:Deuterium; D007700:Kinetics; D008297:Male; D008731:Methoxychlor / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D003903:Deuterium; D008731:Methoxychlor