Premium
Endocannabinoid and Cannabinoid Metabolism by CYP Epoxygenases
Author(s) -
Das Aditi
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb183
Subject(s) - endocannabinoid system , epoxygenase , cannabinoid receptor , anandamide , fatty acid amide hydrolase , cannabinoid , docosahexaenoic acid , chemistry , pharmacology , proinflammatory cytokine , biochemistry , cytochrome p450 , biology , metabolism , polyunsaturated fatty acid , receptor , inflammation , fatty acid , immunology , antagonist
The human body contains endocannabinoids that elicit similar psychoactive and anti‐nociceptive effects to phytocannabinoids in cannabis. Herein we report on the endogenous production of a previously unknown class of ω‐3 PUFA–derived endocannabinoid epoxides that originate from the crosstalk between endocannabinoid and cytochrome P450 (CYP) epoxygenase metabolic pathways. The ω‐3 endocannabinoid epoxides are derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to form epoxyeicosatetraenoic acid‐ethanolamide (EEQ‐EA) and epoxydocosapentaenoic acid‐ethanolamide (EDP‐EA), respectively. Both EEQ‐EAs and EDP‐EAs are endogenously present in rat brain and peripheral organs as determined via targeted lipidomics methods. These metabolites were directly produced by direct epoxygenation of the ω‐ 3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by activated BV‐2 microglial cells, and by human CYP2J2 epoxygenase. Neuroinflammation studies revealed that the terminal epoxides 17,18‐EEQ‐EA and 19,20‐EDP‐EA dose‐dependently abated proinflammatory IL‐6 cytokines while increasing anti‐inflammatory IL‐10 cytokines, in part through cannabinoid receptor‐2 and PPAR gamma activation. Furthermore, the ω‐3 endocannabinoid epoxides 17,18‐EEQ‐EA and 19,20‐EDP‐EA exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the ω‐3 endocannabinoid epoxides' physiological effects are mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. Furthermore, we examined the anti‐inflammatory and anti‐apoptotic role of the six different regioisomers of EDP‐EA (19,20, 16,17‐, 13,14‐, 10,11‐, 7,8‐ & 3,4) that showed wide range of activity towards cannabinoid receptors 1 & 2. In a separate studies we show that cannabinoids inhibit metabolism of endocannabinoids by CYPs. Support or Funding Information American Heart Association Scientist Development grant 15SDG25760064 National Institute of Health (NIH) R01 grant 1R01GM115584‐01A1 and NIH R03 grant 1R03DA042365‐01A1Endocannabinoid metabolism by P450sThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .