CYTOCHROME P4502D ISOZYMES CATALYZE THE 4-HYDROXYLATION OF METHAMPHETAMINE ENANTIOMERS

The 4-hydroxylation of S(+)- and R(-)-methamphetamine by rat liver mic rosomes was examined in Sprague-Dawley and Dark Agouti strains to dete rmine the role of cytochrome P4502D (CYP2D) subfamily isozymes in cata lyzing the reaction. In the study, anti-P450-BTL IgG, bufuralol, and q uinine, a substrate and inhibitors of CYP2D isozymes, respectively, we re found to block similar to 90% of the reaction as catalyzed by micro somes from Sprague-Dawley rats. Reconstituted systems of CYP2D isozyme s purified from rat liver microsomes also mediated the reaction. These observations and the minimal activity found in microsomes from Dark A gouti rats support the notion that methamphetamine, like other phenyli sopropylamine compounds, is oxidized on the 4-position of the aromatic ring by CYP2D isozymes.