In vitro and in vivo interactions of .DELTA.8-tetrahydrocannabinol and its metabolites with hepatic microsomal drug metabolizing enzyme systems of mice.
1981; Pharmaceutical Society of Japan; Volume: 4; Issue: 8 Linguagem: Inglês
10.1248/bpb1978.4.604
ISSN1881-1353
AutoresKazuhito Watanabe, Ikuo Yamamoto, Kazuta Oguri, Hidetoshi Yoshimura,
Tópico(s)Diet, Metabolism, and Disease
ResumoInteractions 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 (Ks) 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.
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