The structure‐activity relationship of lipoxygenase products of long‐chain polyunsaturated fatty acids: Effects on human platelet aggregation

Abstract

The effect of hydroperoxy and hydroxy derivatives of various fatty acids on human platelet aggregation was determined to delineate potencies and structure-activity function. In this regard, the 22-carbon n-3 fatty acids are the most potent inhibitors in comparison to the n-6 lipoxygenase derivatives. Submicromolar levels of the docosapentaenoic (22:5) and especially docosahexaenoic (22:6) n-3 hydroperoxy and hydroxy derivatives specifically antagonize the platelet aggregating effect to arachidonic acid (AA, 20:4n-6) but not that of ADP or collagen. Chain length (22-C > 20-C), double-bond position (n-3 > n-6), and double-bond number (6 > 5 > 4) influence the degree of inhibition of AA-induced aggregation of human platelets. Moreover, significant differences in potency were associated with specific structural aspects of 22:6n-3 lipoxygenase derivatives of 22:6n-3 as follows: functional group (OOH > OH) and positional isomer (14-OOH, 14-OH, 20-OOH > 11-OOH, 17-OOH > 10-OOH > 11-OH, 8-OOH, 7-OOH > 4-OOH).

Oxygenation of polyunsaturated fatty acids and oxidative stress within blood platelets

“…Docosapentaenoic acids, 22:5n-3 and 22:5n-6 are also good substrates of platelet 12-LOX, and the former behaves like DHA with its conversion into 11-and 14-OH derivatives, whereas 22:5n-6 is only converted into 14-OH-22:5 [33]. Both metabolites from 22:5n-3 were shown to inhibit the ArA-induced platelet aggregation [34]. Although 22:5n-3 is generally considered as a minor omega-3 PUFA in marine sources, compared to DHA and EPA, it may increase in vivo as a result of EPA elongation.…”

Mechanisms of action of docosahexaenoic acid in the nervous system

“…This hypothesis was explored extensively after the early reports that cyclooxygenase products of DHA were produced in the rainbow trout gill (79). Early investigations indicated that products made by rat brain were sensitive to LO inhibitors (80)(81)(82)(83). A correction of the trout gill work indicated that the DHA products were not prostaglandins but rather LO products (84).…”

Low-erucic acid rapeseed oil and platelet function

“…Platelets are surrounded by plasma membrane and they have intensive intracellular membrane systems like the dense tubular system. Alterations in the precursor FA pool may also affect platelet function via lipoxygenase products [12]. Phospholipid FA composition may have effects on the physicochemical properties of the cell membranes which can cause alterations in receptor activities and intracellular signalling.…”