Metabolism of icosa-5,11,14-trienoic acid in human platelets and the inhibition of arachidonic acid metabolism in human platelets by icosa-5,8,14-triynoic and icosa-5,11,14-triynoic acids (original) (raw)
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Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1985
Three icosaenoic acids (20: 3(n-6), 20: 5(n-3) and 20: 3(n-9)) which may arise in platelet phospholipids under certain dietary conditions and which may affect platelet functions have been taken up by human platelets. Each acid was pre-coated onto delipidated albumin and then incubated with platelets isolated from their plasma. The distribution study of each acid in cellular lipids revealed that around 80% of the acid taken up was located in phospholipids, of which the bulk was in phosphatidylcholine. The percentage incorporation of each acid into the different glycerophospholipids was similar to their endogenous percentage profiles, therefore simulating the in vivo situation. The icosaenoic acids then incorporated were liberated from phospholipids when platelets were incubated with thrombin or calcium ionophore A23187 and subsequently oxygenated through the cyclooxygenase and/or lipoxygenase pathway. Whereas 20: 3(n-6) was readily converted into cyclooxygenase products, 20: 5(n-3) was more specifically converted into lipoxygenase products, and this latter conversion was comparable to that of 20: 3(n-9) which is not a prostanoid precursor. Finally, only 20:3(n-6)-or 20:5(n-3)-rich platelets exhibited a reduced availability of endogenous arachidonic acid from phospholipids when induced by thrombin. It is concluded that inhibitory polyunsaturated fatty acids (20: 3(n-6) and 20: S(n-3)) could act both by reducing prostaglandin H,/thromboxane A, production from endogenous arachidonic acid and in generating platelet inhibitory substances (cyclooxygenase and/or lipoxygenase products of 20: 3(n-6) and 20: 5(n-3)). On the other hand, 20:3(n-9), a fatty acid which potentiates platelet aggregation through its lipoxygenase end product, could produce sufficient amounts of this compound to enhance the aggregation when platelets are triggered with inducers of phospholipase activity such as thrombin or calcium ionophore.
Biochimica et biophysica acta, 1985
The formation of radiolabelled oxygenated products of arachidonic acid in thrombin-stimulated, [3H]arachidonic acid-prelabelled human platelets is inhibited in a concentration-dependent manner by BW 755C (3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline) or propyl gallate, both of which are combined inhibitors of lipoxygenase and cyclooxygenase. These compounds do not inhibit the thrombin-induced decrease in the radioactivity of platelet phospholipids but, instead, allow the accumulation of free radiolabelled arachidonic acid. Thrombin causes an increase in the levels of free, endogenous palmitic, stearic, oleic, linoleic and arachidonic acids of up to 10 nmol/10(9) platelets. In the presence of BW 755C or propyl gallate, further increases in the level of free arachidonic acid, of 20-50 nmol/10(9) platelets, occur. The enzyme inhibitors do not affect the accumulation of the other free fatty acids. The increase in arachidonic acid is optimal at 1 U/ml thrombin and 60% complete by 1...
Effects of a trans isomer of arachidonic acid on rat platelet aggregation and eicosanoid production
The Journal of Lipid Research
The addition of a trans isomer of arachidonic acid (20:4 A 14truns) to rat platelet suspensions inhibited the aggregation induced by 7.5 p~ of arachidonic acid. This inhibitory effect of 20:4 A 14tram was significant at concentrations of 7.5-22.5 ~L M and the range of inhibition was 20% at an inhibitor/substrate ratio (I/S) 1 to 66% when I/S reached 3. However, the addition of its structural homolog (20:3n-9) or the natural isomer (20:4n-6) did not induce any modification of the platelet aggregation. In parallel, adding 20:4 A 14truns to the platelet significantly decreased thromboxane B2 and 12-hydroxyheptadecatrienoic acid production. In contrast, the 124poxygenase pathway was stimulated, as 12-hydroxyeicosatetraenoic acid production increased up to 55% when the I/S reached 3. 20:3n-9, not being a substrate of the cyclooxygenase, did not induce any significant modification in the formation of thromboxane B2 and 12-hydroxyheptadecatrienoic acid. 20:4 A 14t alone did not induce any platelet aggregation. However, this fatty acid was metabolized to a limited extent into two products that have still to be identified. One of them would be a product of the 12-lipoxygenase pathway. Effects of a trans isomer of arachidonic acid on rat platelet aggregation and eicosanoid production.
The Journal of Nutritional Biochemistry, 1990
We have studied the e fleets of semisynthetic diets eontaining 5% by weight (12% of the energy) of either olive oil (70% oleic acid, OA) or corn oil (58% linoleic acid), or fish oil (Max EPA, containing about 30% eieosapentaenoic, EPA C 20:5 n-3, plus docosahexaenoic, DHA C 22:6 n-3, acids, and less than 2% linoleic acid), fed to male rabbits for a period of five weeks, on plasma and platelet filtty acids and platelet thromboxane formation. Aim of the study was to quantitate the absolute changes of n-6 and n-3 Jatty acid levels in plasma and platelet lipid pools after dietary manipulations and to correlate the effects on eicosanoid-precursor fatty acids with those on platelet thromboxane Jormation. The major diJ.[~'rences were fimnd when comparing the group fed fish oil and depleted linoleic acid vs the other groups. The accumulation of n-3 Jatty acids in various lipid classes was associated with modifications in the distribution of linoleie acid and arachidonic acid in different lipid pools. In platelets, maximal incorporation of n-3 J~tty acids occurred in phosphatidyl ethanolamine, which also participated in most of the total arachidonic acid reduction occurring in platelets, attd linoleie acid, more than archidonic acid, was replaced by n-3.[atty acids in various phospholipids. The archidonie acid content of phosphatidvl choline was unaffected and that of phosphatidyl inositol only marginally reduced. Thromboxane formation by thrombin stimulated platelets did not dia~]?r among the three groups, and this may be related to the minimal changes of arachidonie acid in phosphatidyl choline attd phosphatidyl inositol.
Thrombosis Research, 1986
Eicosapentaenoic acid (EPA) has been reported to have a potent anti-aggregatory activity and to be efficiently metabolized by 12-lipoxygenase, not by cyclooxygenase in platelets. In Vitro effect of 12-lipoxygenase metabolites of EPA on platelet function was studied and compared with those of arachidonic acid (AA). The 12-lipoxygenase metabolites of AA and EPA; 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and 12-hydroperoxyeicosapentaenoic acid (12-HPEPE), and their hydroxy derivatives, 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-hydroxyeicosapentaenoic acid (12-HEPE) were prepared enzymatically using human platelet lysate. These compounds were purified by high performance liquid chromatography and identified by gas chromatographpmass spectrometry. 12-HPETE and 12-HPEPE'inhibited dose-dependently washed human platelet aggregation and serotonin (5-HT) release induced by AA and collagen. The potency of 12-HPEPE was almost equal to that of 12-HPETE. Their hydroxy derivatives, 12-HETE and 12-HEPE were less potent. 12-hydroperoxy derivatives of AA and EPA were the most potent in inhibiting platelet aggregation and 5-HT release among 5-, 12-and 15-hydroperoxy isomers of AA and EPA. The inhibitory effects of 12-HPETE and 12-HPEPE on platelet aggregation were additive.
Lipoxygenase activity of intact human platelets
Prostaglandins, Leukotrienes and Medicine, 1984
The oxygenation by lipoxygenase of different icosaenoic and docosaenoic acids by intact human platelets was studied. The RPLC analysis of the hydroxy compound (8) derived from icosaenoic acids showed that the 12derivatives predominate. The increase of the fatty acid concentration markedly enhanced their oxygenation except for icosapentaenoic acid. The conversion of this acid into its hydroxy derivative rose in the presence of arachidonic acid, probably through both its cycle-oxygenase and lipoxygenase product formation. Since 12-hydroxy-icosaenoic a&ids are modulators of PGH2-induced platelet aggregation, we conclude that the interactions between polyunsaturated fatty acids during their oxygenation by platelet lipoxygenase could be relevant to the regulating activity of dietary fatty acids.
Prostaglandin Endoperoxides. Novel Transformations of Arachidonic Acid in Human Platelets
Proceedings of the National Academy of Sciences, 1974
Arachidonic acid incubated with human platelets was converted into three compounds, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, 12L-hydroxy-5,8,10-heptadecatrienoic acid, and the hemiacetal derivative of 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid. The formation of the two latter compounds from arachidonic acid proceeded by pathways involving the enzyme, fatty acid cyclo-oxygenase, in the initial step and with the prostaglandin endoperoxide, PGG(2), as an intermediate. The first mentioned compound was formed from 12L-hydroperoxy-5,8,10,14-eicosatetraenoic acid, which in turn was formed from arachidonic acid by the action of a novel lipoxygenase. Aspirin and indomethacin inhibited the fatty acid cyclo-oxygenase but not the lipoxygenase, whereas 5,8,11,14-eicosatetraynoic acid inhibited both enzymes. The almost exclusive transformation of the endoperoxide structure into non-prostaglandin derivatives supports the hypothesis that the endoperoxides can participate directly and not by way of the classical prostaglandins in regulation of cell functions. The observed transformations of arachidonic acid in platelets also explain the aggregating effect of this acid.