IN VITRO AND IN VIVO INTERACTIONS OF Δ⁸-TETRAHYDROCANNABINOL AND ITS METABOLITES WITH HEPATIC MICROSOMAL DRUG METABOLIZING ENZYME SYSTEMS OF MICE

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Interactions of Δ⁸-tetrahydrocannabinol (Δ⁸-THC) and its metabolites, 11-hydroxy-Δ⁸-THC, 11-oxo-Δ⁸-THC and Δ⁸-THC-11-oic acid, with hepatic microsomal drug metabolizing enzyme systems were studied in vitro and in vivo using mice. All the cannabinoids used were shown to produce a type I spectral change of cytochrome P-450 in hepatic microsomes. The apparent binding affinities (K_s) for Δ⁸-THC, 11-hydroxy-Δ⁸-THC, 11-oxo-Δ⁸-THC and Δ⁸-THC-11-oic acid were 5.2, 169.6, 33.2 and 148.8μM, respectively. Δ⁸-THC, 11-oxo-Δ⁸-THC and Δ⁸-THC-11-oic acid (100μM) caused a significant stimulation of NADPH oxidation in vitro with microsomes. In addition, Δ⁸-THC (20, 40 and 80μM) markedly inhibited p-nitroanisole O-demethylase and aniline hydroxylase in microsomes. 11-Hydroxy-Δ⁸-THC and 11-oxo-Δ⁸-THC also showed the inhibitory effect, but to lesser extents. Furthermore, single pretreatments with Δ⁸-THC and 11-oxo-Δ⁸-THC (30 mg/kg, i.v.) significantly decreased activities of p-nitroanisole O-demethylase and aniline hydroxylase in hepatic microsomes, accompanying a decrease of cytochrome P-450 content in case of Δ⁸-THC. On the other hand, all these pretreatments except for that with Δ⁸-THC-11-oic acid showed a stimulatory effect on p-nitrophenol glucuronidation with hepatic microsomes, in contrast to an inhibitory effect in vitro.