The structure-activity relationship of lipoxygenase products of long-chain polyunsaturated fatty acids: effects on human platelet aggregation.
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).
Karanian
J W
JW
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, Maryland 20852, USA.
Kim
H Y
HY
Salem
N
N
D016718:Arachidonic Acid / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008084:Lipoxygenase / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D005231:Fatty Acids, Unsaturated; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D008084:Lipoxygenase