The endocannabinoid anandamide is a substrate of cytochrome P450 2D6

Abstract

The endocannabinoid anandamide, an arachidonic acid derivative, activates the cannabinoid receptors CB1 and CB2. These receptors and the enzymes involved in the synthesis and inactivation of their endogenous ligands represent novel targets for the treatment of many nervous system and peripheral disorders. We recently demonstrated that anandamide is a substrate for the liver and kidney cytochrome P450 (CYP) enzymes 3A4 and 4F2. Several CYP isoforms are present in the brain and have important roles in the oxidation of endogenous substrates. The objective of the current studies was to determine if anandamide is a substrate for the human polymorphic CYP 2D6, one of the major CYP isoforms in human brain. We found that recombinant CYP 2D6 converted anandamide to 20‐hydroxyeicosatetraenoic acid ethanolamide (20‐HETE‐EA) and 5,6‐, 8,9‐, 11,12‐, and 14,15‐epoxyeicosatrienoic acid ethanolamides (EET‐EAs) with apparent Km values of 1–2 μM. CYP 2D6 further metabolized the epoxides of anandamide to form several di‐oxygenated derivatives. To our knowledge, anandamide and its epoxides are the first eicosanoid molecules to be identified as CYP2D6 substrates, raising the possibility that this enzyme could be involved in the metabolism of other endogenous mediators with similar structural properties. Supported in part by the National Institutes of Health (Grants CA‐16954 and T32 GM007767).