Possible involvement of Cyp3a enzymes in the metabolism of tetrahydrocannabinols by mouse brain microsomes

Δ⁸-Tetrahydrocannabinol (THC) and Δ⁹-THC were mainly oxidized on the pentyl side chain at the 4′-position by mouse brain microsomes. 5′-Hydroxy-THCs were also formed as minor metabolites. However, 11-hydroxy metabolites of THCs, which are major metabolites of the cannabinoids produced by mouse hepatic microsomes, were not detectable as the metabolites formed by mouse brain microsomes. Cytochrome P450 (CYP) enzymes involved in the brain microsomal metabolism of Δ⁸-THC and Δ⁹-THC were identified by using CYP-selective inhibitors. The 4′- and 5′-hydroxylations of THCs were strongly inhibited by ketoconazole and troleandomycin, the known inhibitors of CYP3A enzymes, but not by other isozyme-selective inhibitors, such as 7,8-benzoflavone (CYP1A), quinidine (CYP2D), and sulfaphenazole (CYP2C). These results indicate that Cyp3a enzymes are responsible at least in part for the metabolism of Δ⁸-THC and Δ⁹-THC by mouse brain microsomes. Our present results using mouse brain seem to support the idea that the mode of THC metabolism by CYP enzymes in human brain is different from that in human liver.