Characterization of microsomal alcohol oxygenase catalyzing the oxidation of 7-hydroxy-Δ⁸-tetrahydrocannabinol to 7-oxo-Δ⁸- tetrahydrocannabinol in rat liver

The formation of 7-oxo-Δ⁸-tetrahydrocannabinol (7-oxo-Δ⁸-THC) from 7β-hydroxy-Δ⁸-THC was found in hepatic microsomes of rats. The activity was stereoselective and about 3-fold higher than that from 7α-hydroxy-Δ⁸- THC. The oxidative activity of 7α- and 7β-hydroxy-Δ⁸-THC to 7-oxo-Δ⁸- THC was significantly higher in male than in female, and significantly enhanced by both dexamethasone and phenobarbital, and then inhibited up to about 20% of the control value by antibody against P450GPF-B, presumably a member of the 3A subfamily, a major enzyme responsible for the formation of 7-oxo-Δ⁸-THC in guinea pigs. This antibody also inhibited the formation of 7α- and 7β-hydroxy-Δ⁸-THC, and 7-oxo-Δ⁸-THC from Δ⁸-THC by hepatic microsomes of rats. These results indicate that there is a sex-related difference in the oxidation of 7-hydroxy-Δ⁸-THC to 7-oxo-Δ⁸-THC and the reaction is mainly catalyzed by P450 enzyme(s) belonging to the 3A subfamily as major enzyme(s) of microsomal alcohol oxygenase in rats.