In vivo effects of tetrahydrocannabinols and their eight monooxygenated metabolites on the hepatic microsomal drug-metabolizing enzyme systems of mice.

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Abstract
In vivo effects of tetrahydrocannabinols (THCs) and their eight monooxygenated metabolites on the hepatic microsomal drug-metabolizing enzymes in mice were studied. .DELTA.8-THC and its metabolites (7 .alpha.-hydroxy- 7 .beta.-hydroxy- and 7-oxo-.DELTA.8-THC, and 8.alpha., 9 .alpha.- and 8.beta., 9.beta.-epoxyhexahydrocannabinol) tended to increase the enzyme contents or activities except for 7 .beta.-hydroxy-.DELTA.8-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-.DELTA.8-THC, 8.alpha., 9.alpha.- and 8.beta., 9.beta.-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 8.beta., 9.beta.-epoxyhexahydrocannabinol on cytochrome P-450 was not statistically significant. 7 .beta.-Hydroxy-.DELTA.8-THC significantly increased nicotinamide adenine dinucleotide phospate (NADPH)-cytochrome c reductase and aniline hydroxylase activiies 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, .DELTA.9-THC and its metabolites (8.alpha.-hydroxy-, 8.beta.-hydroxy- and 8-oxo-.DELTA.9-THC) did not significantly affect the microsomal enzymes by both treatments except that the single administration of 8.alpha.-hydroxy-.DELTA.9-THC and the subchronic treatment of .DELTA.9-THC significantly decreased NADPH-cytochrome c reductase activity. These results indicated that monooxygenated metabolites of .DELTA.8-and .DELTA.9-THC affect the hepatic microsomal drug-metabolizing enyzme systems of mice differently.