MICROSOMAL CYTOCHROME P450-MEDIATED LIVER AND BRAIN ANANDAMIDE METABOLISM

Anandamide (AN) is an arachidonic acid congener, found in the brain, t hat binds to the cannabinoid receptor and elicits cannabinoid-like pha rmacological activity. Cytochromes P450 (P450s) are known to oxidize a rachidonic acid to a wide variety of metabolites, yielding many physio logically potent compounds. To determine if AN could be similarly oxid ized by P450s, its metabolism by mouse liver and brain microsomes was examined. Mouse hepatic microsomal incubation of AN with NADPH resulte d in the generation of at least 20 metabolites, determined after HPLC separation by increased UV-absorbance at 205 nm. Pretreatment of mice with various P450 inducers resulted in increased hepatic microsomal fo rmation of several AN metabolites, with dexamethasone being the most e ffective inducer. Phenobarbital pretreatment resulted in a metabolic p rofile similar to that observed after dexamethasone pretreatment, wher eas 3-methylcholanthrene pretreatment selectively increased the format ion of several other metabolites. Clofibrate pretreatment had no effec t on hepatic AN metabolism. Polyclonal antibodies prepared against mou se hepatic P450 3A inhibited the formation of several AN metabolites b y hepatic microsomes from untreated mice as well as the formation of t hose metabolites found to be increased after dexamethasone pretreatmen t. AN metabolism by brain microsomes resulted in the formation of two NADPH- and protein-dependent metabolites. Hepatic P450 3A antibody par tially inhibited the formation of only one of these metabolites. Thus, P450 3A is a major contributor to AN metabolism in the liver but not in the brain. The physiological consequences of P450-mediated AN metab olism remain to be determined.