Rat liver microsomal enzyme catalyzed oxidation of 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine

Abstract

NADPH supplemented rat liver microsomal enzyme preparations catalyze the conversion of 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine to the p-hydroxyphenyl (low yield), descyclopropyl (high yield) and 2,3-dihydropyridinium and, subsequently, pyridinium (intermediary yield) metabolites. When the methine proton of the cyclopropyl group was replaced with a deuteron, a normal deuterium isotope effect (1.4) was observed on the formation of the decyclopropylated metabolite and an inverse isotope effect (0.6) on the dihydropyridinium metabolite. A larger deuterium isotope effect (3.6) was observed on the ring α-carbon oxidation pathway with the 2,2,6,6- d 4 analogue as substrate. These results and the observation that the ratios of the rates of these two α-carbon oxidation pathways are independent of initial substrate concentrations suggest that both pathways are catalyzed by the same active site of one form of P450. These transformations are discussed in terms of metabolic pathways that have been proposed for the cytochrome P450 catalyzed α-carbon oxidation of amines.