Epoxydocosapentaenoic acid
Epoxide docosapentaenoic acids (epoxydocosapentaenoic acids, EDPs, or EpDPEs) are metabolites of the 22-carbon straight-chain
Structure
EDPs are epoxide eicosapentaenoic acid metabolites of DHA. DHA has 6 cis (see Cis–trans isomerism) double bonds each one of which is located between carbons 4-5, 7-8, 10-11, 13-14, 16-17, or 19-20. Cytochrome P450 epoxygenases attack any one of these double bounds to form a respective docosapentaenoic acid (DPA) epoxide regioisomer (see Structural isomer § Position isomerism (regioisomerism)). A given epoxygenase may therefore convert DHA to 4,5-EDP (i.e. 4,5-epoxy-7Z,10Z,13Z,16Z,19Z-DPA), 7,8-EDP (i.e. 7,8-epoxy-4Z,10Z,13Z,16Z,19Z-DPA), 10,11-EDP (i.e. 10,11-epoxy-4Z,7Z,13Z,16Z,19Z-DPA), 13,14-EDP (i.e. 13,14-epoxy-4Z,7Z,10Z,16Z,19Z-DPA), 16,17-EDP (i.e. 16,17-epoxy-4Z,7Z,10Z,13Z,19Z-DPA, or 19,20-EDP (i.e. 19,20-epoxy-4Z, 7Z,10Z,13Z,16Z-DPA. The epoxygenase enzymes generally form both R/S enantiomers at each former double bound position; for example, cytochrome P450 epoxidases attack DHA at the 16,17-double bond position to form two epoxide enantiomers, 16R,17S-EDP and 16S,17S-EDP.[2] The 4,5-EDP metabolite is unstable and generally not detected among the EDP formed by cells.[3]
Production
Enzymes of the cytochrome P450 (CYP) superfamily that are classified as epoxygenases based on their ability to metabolize PUFA, particularly arachidonic acid, to epoxides include: CYP1A, CYP2B, CYP2C, CYP2E, CYP2J, and within the CYP3A subfamily, CYP3A4. In humans,
The EDPs are commonly made by the stimulation of specific cell types by the same mechanisms which produce EETs (see Epoxyeicosatrienoic acid). That is, cell stimulation causes DHA to be released from the sn-2 position of their membrane-bound cellular phospholipid pools through the action of a phospholipase A2-type enzyme and the subsequent attack of the released DHA by CYP450 epoxidases. It is notable that the consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans. Indeed, this rise in EDP (and EEQ) levels in humans is by far the most prominent change in the profile of PUFA metabolites caused by dietary omega-3 fatty acids and, it is suggested, may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids.[1][13]
EDP metabolism
Similar to EETs (see
In addition to the sEH pathway, EDPs, similar to the EETs, may be acylated into phospholipids in an acylation-like reaction; this pathway may serve to limit the action of EETs or store them for future release.[2] Finally, again similar to the EETs, EDPs are subject to inactivation by being further metabolized by beta oxidation.[17]
Clinical significance
EDPs have not be studied nearly as well as the EETs. This is particularly the case for animal studies into their potential clinical significance. In comparison to a selection of the many activities attributed to the EETs (see Epoxyeicosatrienoic acid), animal studies reported to date find that certain EDPs (16,17-EDP and 19,20-EDP have been most often examined) are: 1) more potent than EETs in decreasing hypertension and pain perception; 2) more potent than or at least equal in potency to the EETs in suppressing inflammation; and 3) act oppositely from the EETs in that EDPs inhibit angiogenesis, endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems.[1][3][16][17] As indicated in the Metabolism section, consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans and in humans is by far the most prominent change in the profile of PUFA metabolites caused by dietary omega-3 fatty acids. Hence, the metabolism of DHA to EDPs (and EPA to EEQs) may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids.[1][13][17]