Mammalian platelets contain an active lipoxygenase and are capable of enzymatically producing a number of n-6 and n-3 hydroxy fatty acids. Sub- micromolar levels of the n-3 hydroxy fatty acids specifically antagonize both the contractile effects of a thromboxane mimetic, U46619, and its platelet aggregating effect. In addition, OH-22:6n3 reduces thromboxane- induced increases in cerebral blood flow of the rat. The hydroxy fatty acids specifically interact with the thromboxane receptor in both platelet and smooth muscle. Analysis of binding parameters indicates these derivatives induce a marked decrease in the affinity of the receptor for thromboxane with a mild change in the number of receptor sites. Moreover, these metabolites stimulate the production of lipoxygenase products from airway tissue, neutrophils and monocytes in a dose-dependent manner. Hydroxy-induced contraction of the airway smooth muscle is, in part, due to the endogenously produced contractile leukotrienes. The 22-carbon n-3 hydroxy fatty acids are the most potent biologically in comparison to the n-6 hydroxy fatty acids and their parent fatty acids. Both dietary fish oil and short-term ethanol exposure increase the production of these n-3 metabolites and correlate with a decrease in platelet and vascular smooth muscle function. Chronic ethanol exposure depletes the content of parent fatty acids and the capacity to produce these n-3 derivatives. Dietary enrichment with the n-3 fatty acids counters the effects of long-term ethanol exposure. These permutations modify the hydroxy fatty acid profile and correlate with changes in thromboxane-mediated responses.
