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 omega3 essential fatty acids. Recent work has confirmed the roles of omega3 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 A3 from EPA via cyclooxygenase-1. A second major consequence of elevated EPA/AA ratios is significantly increased production of 3-series PGs, including PGE3, 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 PGE3 than to PGE2; this difference may underlie the ability of omega3 fatty acids to mitigate inflammation and tumorigenesis.