Effect of repeated administration of 11-hydroxy- Δ8-tetrahydrocannabinol, an active metabolite of Δ8tetrahydrocannabinol, on the hepatic microsomal drug-metabolizing enzyme system of mice

Abstract

The effects of Δ 8-tetrahydrocannabinol (Δ 8-THC) and its major and active metabolite, 11-hydroxy- Δ 8-tetrahydrocannabinol (11-OH- Δ 8-THC), on the hepatic microsomal drug-metabolizing enzyme system were studied in mice. The repeated administration of 11-OH- Δ 8-THC (5 mg/kg/day, i.v.) for 3 or 7 days increased significantly the activities of aniline hydroxylase and p-nitroanisole O-demethylase. By the same treatment, cytochrome P-450 content (3 days) or NADPH-cytochrome c reductase activity (7 days) was also increased significantly. The treatment with Δ 8-THC for 7 days (5 mg/kg/day, i.v.) significantly increased aniline hydroxylase only. 11-OH- Δ 8-THC increased the V max, but not the K m , values for both drug-metabolizing enzymes, whereas Δ 8-THC decreased significantly the K m , value (270 μM) for p-nitroanisole O-demethylase as compared with the control (398 μM). Repeated administration of these cannabinoids for 7 days also increased the metabolism of Δ 8-THC by hepatic microsomes; this was attributed to an enhanced formation of 11-OH- Δ 8-THC. In contrast, microsomal formation of 7α-OH- Δ 8-THC was decreased significantly by treatment with Δ 8-THC. 11-OH- Δ 8-THC, but not Δ 8-THC, treatment increased the metabolism of 11-OH- Δ 8-THC by hepatic microsomes. These findings indicate that Δ 8-THC and 11-OH- Δ 8-THC treatment can induce hepatic microsomal drug-metabolizing enzymes and affect differently the catalytic properties of the enzymes.