Effects of two cannabinoids on hepatic microsomal cytochrome P-450.
The effects of cannabidiol (CBD) and delta 9-tetrahydrocannabinol (delta 9-THC) on the synthesis and degradation of hepatic microsomal cytochrome P-450 were studied in mice. Cannabinoids used (10, 50 and 100 mg/kg, i.p.) did not affect delta-aminolevulinic acid synthetase activity in the liver. delta 9-THC-treatment (10, 50 and 100 mg/kg, i.p.) markedly stimulated heme oxygenase activity in hepatic 18000 X g supernatant fractions in a dose-dependent manner, whereas CBD-treatment was without effect. In vitro experiments, CBD and delta 9-THC (40 to 160 microM) markedly inhibited nicotinamide adenine dinucleotide phosphate (NADPH)-induced lipid peroxidation in hepatic microsomes. When CBD was incubated with the hepatic microsomes in the presence of an NADPH-generating system, cytochrome P-450 content decreased significantly. However, delta 9-THC showed no effects in similar experiments. The rate of decrease in the cytochrome P-450 content using CBD (160 microM) was 0.212 nmol/mg protein/20 min in microsomes from control mice. This value increased significantly in microsomes from phenobarbital-treated mice (0.792 nmol/mg protein/20 min) but not in those from 3-methylcholanthrene-treated mice (0.190 nmol/mg protein/20 min). The metabolic rate (per nmol cytochrome P-450) of CBD was also increased significantly by phenobarbital-treatment but not by 3-methylcholanthrene-treatment. These results suggest that CBD metabolites rather than CBD itself, play some role in the decreasing effect on cytochrome P-450 content in the hepatic microsomes in vitro, and that the microsomal formation of reactive metabolite of CBD is increased by phenobarbital-treatment.
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology
D002186:Cannabinoids; D008054:Lipid Peroxides; D002185:Cannabidiol; D008315:Malondialdehyde; D008748:Methylcholanthrene; D013759:Dronabinol; D003577:Cytochrome P-450 Enzyme System; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; D010634:Phenobarbital