In vitro and in vivo interactions of delta 8-tetra-hydrocannabinol and its metabolites with hepatic microsomal drug metabolizing enzyme systems of mice.

Interactions of delta 8-tetrahydrocannabinol (delta 8-THC) and its metabolites, 11-hydroxy-delta 8-THC, 11-oxo-delta 8-THC and delta 8-THC-11-oic acid, with hepatic microsomal drug metabolizing enzyme 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 (Ks) for delta 8-THC, 11-hydroxy-delta 8-THC, 11-oxo-delta 8-THC and delta 8-THC-11-oic acid were 5.2, 169.6, 33.2 and 148.8 microM, respectively. delta 8-THC, 11-oxo-delta 8-THC and delta 8-THC-11-oic acid (100 microM) caused a significant stimulation of NADPH oxidation in vitro with microsomes. In addition, delta 8-THC (20, 40 and 80 microM) markedly inhibited p-nitroanisole O-demethylase and aniline hydroxylase in microsomes. 11-Hydroxy-delta 8-THC and 11-oxo-delta 8-THC also showed the inhibitory effect, but to lesser extents. Furthermore, single pretreatments with delta 8-THC and 11-oxo-delta 8-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 delta 8-THC. On the other hand, all these pretreatments except for that with delta 8-THC-11-oic acid showed a stimulatory effect on p-nitrophenol glucuronidation with hepatic microsomes, in contrast to an inhibitory effect in vitro.