Metabolism of Anandamide by Human Cytochrome P450 2J2 in the Reconstituted System and Human Intestinal Microsomes.

According to the Centers for Disease Control and Prevention, the incidence of inflammatory bowel diseases (IBD) is about 1 in 250 people in the United States. The disease is characterized by chronic or reoccurring inflammation of the gut. Due to the localization of the endocannabinoid system in the gastrointestinal tract, it may be a potential pharmacological target for the treatment of IBD and other diseases. Fatty acid amide hydrolase (FAAH) is a potential candidate because it is upregulated in IBD. FAAH hydrolyzes and, as a consequence, inactivates anandamide, a prominent endocannabinoid. Inhibition of FAAH would lead to increases in the amount of anandamide oxidized by cytochrome P450s (CYP450). CYP2J2, the major CYP450 epoxygenase expressed in the heart, is also expressed in the intestine and has previously been reported to oxidize anandamide. We have investigated the possibility that it may play a role in anandamide metabolism in the gut. We demonstrate here that purified human CYP2J2 metabolizes AEA to form the 20-hydroxyeicosatetraenoic acid ethanolamide (HETE-EA) and several epoxygenated products including the 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EET-EAs), in the reconstituted system. Kinetic studies suggest that the KM values for these products range from approximately 10-468 μM and the kcat values range from 0.2-23.3 pmol/min/pmol of CYP450. Human intestinal microsomes, which express CYP2J2, metabolize AEA to give the 5,6-, 8,9-, and 11,12-EET-EAs as well as 20-HETE-EA. Studies using specific P450 inhibitors suggest that although CYP2J2 metabolizes AEA, it is not the primary CYP450 responsible for AEA metabolism in human intestines.
The American Society for Pharmacology and Experimental Therapeutics.