Abstract

Hepatic microsomal metabolism of delta 1-tetrahydrocannabinol (THC) has been extensively studied in many rodent species, but there have been few reports describing such metabolism in humans. Because several THC metabolites are known to be pharmacologically active, identifying the P-450 subfamilies responsible for their formation is of clinical importance. We have found that, in addition to catalyzing the formation of significant amounts of 7-hydroxy-THC, hepatic microsomes from nine human livers also formed 6 beta-hydroxy-THC at approximately the same rate. In addition, 1 alpha,2 alpha-epoxyhexahydrocannabinol (EHHC) was formed at approximately one-third the rate of 7-hydroxy- and 6 beta-hydroxy-THC, and small amounts of 6 alpha-hydroxy- and 6-keto-THC were also found. Immunoinhibition studies with antibodies raised against human hepatic P-450 2C9, or a mouse hepatic P-450 isozyme belonging to the P-450 3A subfamily, revealed that P-450 2C9 catalyzed the formation of 7-hydroxy-THC, whereas P-450 3A catalyzed the formation of 6 beta-hydroxy-THC, EHHC, and the relatively minor metabolites. In contrast, antibodies raised against human P-450 2C8 had no affect on human microsomal THC hydroxylation. Excellent correlations were found between hepatic microsomal P-450 2C9 and 3A content and 7-hydroxy- and 6 beta-hydroxy-THC formation, respectively. In addition, purified P-450 2C9 catalyzed the formation of 7-hydroxy-THC at a 7-fold higher rate than that observed with microsomes. Microsomal 7-hydroxy-THC formation varied less than 5-fold between the livers, suggesting that this activity is normally expressed and probably not subject to environmental influences.(ABSTRACT TRUNCATED AT 250 WORDS)