Cyclooxygenases, peroxide tone and the allure of fish oil

Skepticism about the health benefits of fish oil is largely the result of our incomplete understanding of the biochemistry of omega 3 essential fatty acids. Recent work has confirmed the roles of omega 3 fatty acids in gene transcription and signal transduction, and has given insight into the effects of eicosapentaenoic acid (EPA) and the EPA/arachidonic acid (AA) ratio on prostanoid (PG) metabolism and function. One pronounced effect of fish-oil-induced increases in EPA/AA ratios is decreased PG formation from AA via cyclooxygenase-1, because EPA inhibits this isoform. In addition, cells lacking endogenous alkyl-peroxide-generating systems and thus having a low 'peroxide tone' cannot oxygenate EPA via cyclooxygenase-1. Platelets, however, which are equipped with a lipoxygenase that can produce an abundance of hydroperoxide from AA, can form small amounts of thromboxane A(3) from EPA via cyclooxygenase-1. A second major consequence of elevated EPA/AA ratios is significantly increased production of 3-series PGs, including PGE(3), via cyclooxygenase-2. There are four PGE receptor subtypes and at least one of these types - not yet identified - has a significantly different response to PGE(3) than to PGE(2); this difference may underlie the ability of omega 3 fatty acids to mitigate inflammation and tumorigenesis.