IN VIVO EFFECTS OF TETRAHYDROCANNABINOLS AND THEIR EIGHT MONOOXYGENATED METABOLITES ON THE HEPATIC MICROSOMAL DRUG-METABOLIZING ENZYME SYSTEMS OF MICE

Abstract

In vivo effects of tetrahydrocannabinols (THCs) and their eight monooxygenated metabolites on the hepatic microsomal drug-metabolizing enzymes in mice were studied. Δ⁸-THC and its metabolites (7α-hydroxy-, 7β-hydroxy- and 7-oxo-Δ⁸-THC, and 8α, 9α- and 8β, 9β-epoxyhexahydrocannabinol) tended to increase the enzyme contents or activities except for 7β-hydroxy-Δ⁸-THC which affected the microsomal enzymes in a different manner between the single and subchronic treatments. Single administration (5 mg/kg, i.v.) of 7-oxo-Δ⁸-THC, 8α, 9α- and 8β, 9β-epoxyhexahydrocannabinol led to a significant increase in hepatic microsomal p-nitroanisole O-demethylase and aniline hydroxylase activities accompanying a significant increase in cytochrome P-450 content in hepatic microsomes. The same results were obtained with subchronic treatment of mice with these metabolites (5 mg/kg/d, i.v. for 7 d), although the effect of 8β, 9β-epoxyhexahydrocannabinol on cytochrome P-450 was not statistically significant. 7β-Hydroxy-Δ⁸-THC significantly increased nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome creductase and aniline hydroxylase activities by single administration, while the metabolite significantly decreased the contents of cytochrome b₅ and P-450 and p-nitrophenol uridine diphosphate-glucuronyltransferase activity by the subchronic treatment. In contrast, Δ⁹-THC and its metabolites (8α-hydroxy-, 8β-hydroxy- and 8-oxo-Δ⁹-THC) did not significantly affect the microsomal enzymes by both treatments except that the single administration of 8α-hydroxy-Δ⁹-THC and the subchronic treatment of Δ⁹-THC significantly decreased NADPH-cytochrome c reductase activity. These results indicated that monooxygenated metabolites of Δ⁸- and Δ⁹-THC affect the hepatic microsomal drug-metabolizing enzyme systems of mice differently.