Epoxygenase metabolites of docosahexaenoic and eicosapentaenoic acids inhibit platelet aggregation at concentrations below those affecting thromboxane synthesis.
Docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids are the major n-3 fatty acids in fish oils. When either DHA or EPA is added to platelet suspensions, aggregation and thromboxane synthesis are both suppressed. However, when DHA or EPA is provided as a dietary supplement, only platelet aggregation is impaired during the early phase of the diet. In the present study, we examined whether cytochrome P-450 epoxygenase metabolites of DHA/EPA can inhibit platelet aggregation without affecting thromboxane synthesis. Epoxide regioisomers of DHA, EPA and arachidonic acid (AA) and their corresponding diol hydrolysis products were chemically synthesized. Aggregation and thromboxane A2 formation were induced in washed-platelet suspensions by addition of AA and measured by turbidometry and radioimmunoassay. The ranges of aggregation inhibition (IC50) by the families of epoxide regioisomers derived from DHA, EPA and AA were 0.7 to 1.5, 3.2 to 5.4 and 1.0 to 4.0 microM, respectively. The IC50 values for the DHA, EPA and AA diol families ranged from 3.4 to 11.7, from 31 to 173 and from 16 to 86 microM, respectively. Hydrolysis greatly reduced the capacity of EPA and AA epoxides, but not of DHA epoxides, to inhibit platelet aggregation. The IC50 values of DHA, EPA and AA epoxide families for thromboxane synthesis ranged from 6 to 100, from 10 to 100 and from 1.7 to 9.1 microM, respectively. Thus, in contrast to AA epoxides, all the DHA and EPA epoxides inhibited platelet aggregation at concentrations below those that affected thromboxane synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
VanRollins
M
M
Department of Internal Medicine, University of Iowa, Iowa City, USA.
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000378:metabolism*; D004852:Epoxy Compounds / Q000494:pharmacology*; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013931:Thromboxanes / Q000096:biosynthesis*
D004852:Epoxy Compounds; D010975:Platelet Aggregation Inhibitors; D013931:Thromboxanes; D004281:Docosahexaenoic Acids; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D015118:Eicosapentaenoic Acid; D015126:8,11,14-Eicosatrienoic Acid