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.
D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D013759:Dronabinol / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases; D009575:Nitroanisole O-Demethylase / Q000378:metabolism*; D009596:Nitrophenols / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism*; D013053:Spectrophotometry
D005965:Glucuronates; D009596:Nitrophenols; D013759:Dronabinol; D003577:Cytochrome P-450 Enzyme System; D009575:Nitroanisole O-Demethylase; D010088:Oxidoreductases; D000815:Aniline Hydroxylase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases