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

The effects of Δ⁸-tetrahydrocannabinol (Δ⁸-THC) and its major and active metabolite, 11-hydroxy-Δ⁸-tetrahydrocannabinol (11-OH-Δ⁸-THC), on the hepatic microsomal drug-metabolizing enzyme system were studied in mice. The repeated administration of 11-OH-Δ⁸-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 Δ⁸-THC for 7 days (5 mg/kg/day, i.v.) significantly increased aniline hydroxylase only. 11-OH-Δ⁸-THC increased the V_max, but not the K_m, values for both drug-metabolizing enzymes, whereas Δ⁸-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 Δ⁸-THC by hepatic microsomes; this was attributed to an enhanced formation of 11-OH-Δ⁸-THC. In contrast, microsomal formation of 7α-OH-Δ⁸-THC was decreased significantly by treatment with Δ⁸-THC. 11-OH-Δ⁸-THC, but not Δ⁸-THC, treatment increased the metabolism of 11-OH-Δ⁸-THC by hepatic microsomes. These findings indicate that Δ⁸-THC and 11-OH-Δ⁸-THC treatment can induce hepatic microsomal drug-metabolizing enzymes and affect differently the catalytic properties of the enzymes.