Chronic treatment with the endocannabinoid anandamide increases cytochrome P450 metabolizing system in the rat

The aim of this work was to investigate the effects of single and repeated administration of the endogenous cannabinoid anandamide (20 mg/kg i.p.) on cytochrome P450-mediated biotransformation in the rat. In liver microsomes from chronically treated rats, an increase in cytochrome P450 content and in the activity and immunoreactivity of cytochrome P450 reductase was detected. Immunoblot analysis of the hepatic microsomal proteins revealed an increase in the relative level of cytochrome P450 2B1/2 and 3A2. The activity of monooxygenase enzymes linked to specific cytochrome P450 isoforms was significantly enhanced. This increase in the content and activity of the cytochrome P450 system was also seen in liver microsomes from acutely treated rats; however, these increases were smaller than those seen after prolonged treatment. After acute treatment, the brain cytochrome P450 and b(5) content was increased, whereas after chronic treatment, only that of b(5) was enhanced. Cytochrome P450 reductase activity and its relative abundance were increased only in the brains of chronically treated rats. The present findings demonstrate that anandamide administration increased the metabolic activity of the cytochrome P450 system in rat liver and brain.