In vivo and in vitro effects of Δ 9-tetrahydrocannabinol on rat liver microsomal drug-metabolizing enzymes

Abstract

The in vivo and in vitro effects of Δ 9-tetrahydrocannabinol ( Δ 9-THC) on rat liver microsomal dimethylaniline- N-demethylase, p-nitroanisole- O-demethylase and aniline hydroxylase activities were studied. In vivo acute administration of Δ 9-THC produced a marked inhibitory effect of these drug-metabolizing enzyme activities at the higher dose (50 mg/kg) after 6 hr of ip injection. The inhibition was of mixed type for the two demethylases and noncompetitive in case of aniline hydroxylase, whereas comparatively fewer inhibitory effects on these enzyme activities were observed at the lower dose (10 mg/kg). Chronic treatment with Δ 9-THC for 21 days (10 mg/kg/day) competitively inhibited the N- and O-demethylase activities but had no inhibitory effect on aniline hydroxylase. Under in vitro conditions of drug treatment at doses of 2, 4, and 8 μg/mg of protein, two demethylase activities were found to be inhibited in a competitive manner whereas comparatively less and mixed type of inhibition was observed with aniline hydroxylase only at higher doses of the drug. These results suggest that Δ 9-THC changes the conformation of the hepatic microsomal membrane in a characteristic way, and there exists a qualitative difference between the two substrate-binding sites of the microsomal membrane regarding their interaction with a highly lipophilic drug like Δ 9-THC.