Metabolism of omega-6 arachidonic acid by cytochrome P450 (CYP) epoxygenases yields epoxy lipids including epoxyeicosatrienoic acids (EETs). These transformation products are pro-angiogenic and enhance tumor growth and metastasis by stimulation of tumor angiogenesis. By contrast, CYP epoxygenase metabolism of omega-3 dietary fatty acids, specifically decosahexaenoic acid, produces epoxydocosapentanoic acids (EDPs) which inhibit angiogenesis, decrease primary tumor growth, and slow cancer cell metastasis. The mechanisms by which omega-3 and omega-6 fatty acids affect angiogenesis and cancer are still not entirely understood. Preliminary evidence has suggested that EETs may be transformed by cylooxygenase (COX) enzymes to form products that are several times more angiogenic than EETs themselves. The ability of EDPs to react with COX is unknown. This study aims to further understand the opposing mechanisms of EETs and EDPs on angiogenesis and progression of cancer, by elucidating a novel lipid metabolism pathway controlled by CYP and COX enzymes. The relative affinities of EETs and EDPs as substrates for COX enzymes were tested using a COX kinetic assay. Of all the EET and EDP regioisomers, 8,9 EET and 7,8 EDP were most active with COX, with Km values of 8 � 6 �M (COX-1), 5 � 1 �M (COX-2) for 8,9 EET, and 3 � 0.3 �M  (COX-2) for 7,8 EDP. Additionally, preliminary product analysis from this metabolic pathway was done using LC-ToF-MS, indicating a variety of novel transformation products having peroxide, diol, and hydroxyl functional groups. These results may support the findings surrounding the opposing activity of EETs and EDPs, through their formation of potentially biological active COX metabolites. Omega-3 fatty acids are increasingly being marketed as dietary supplements, therefore it is relevant and timely to further understand the mechanism that may be associated with the cancer biology of these compounds.

Metabolism of epoxy omega-3 and -6 fatty acids through cyclooxygenase: A novel lipid regulatory pathway

248th National Meeting (2014)

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