Metabolites Of Polyunsaturated Fatty Acids Research Articles

Effects of selenium-deficient diets on the production of prostaglandins and other oxygenated metabolites of arachidonic acid and linoleic acid by rat and rabbit aortae

Selenium is an essential component of glutathione peroxidase, which reduces free and esterified hydroperoxides of polyunsaturated fatty acids. Adequate glutathione peroxidase activity could be important for the maintenance of prostacyclin synthesis by blood vessels, since hydroperoxides can inhibit the formation of this substance. We have investigated the effects of dietary selenium deficiency on glutathione peroxidase activity and the synthesis of 6-oxoprostaglandin F 1α and monohydroxy and trihydroxy metabolites of polyunsaturated fatty acids by aorta. The latter products can be formed either by the actions of cyclooxygenase or lipoxygenase or by lipid peroxidation. Aortic glutathione peroxidase activity was reduced by over 80% by feeding rats a selenium-deficient diet for 4 weeks, and to undetectable levels after 6 weeks. There were no appreciable differences in the levels of free and esterified oxygenated metabolites of linoleic acid or arachidonic acid between the control and treated groups after 4 weeks. However, after 6 weeks, there were modest, but statistically significant reductions in the formation of 6-oxoprostaglandin F 1α and monohydroxy products formed by cyclooxygenase. On the other hand, the amounts of esterified 18:2 metabolites appeared to be higher in aortae from animals on the selenium-deficient diet, although only the increase in esterified 9-hydroxy-10,12-octadecadienoic acid was statistically significant. These results suggest that selenium deficiency can affect the formation of prostacyclin and other oxygenated metabolites of polyunsaturated fatty acids by aorta, possibly by increasing lipid peroxidation. However, the differences between control and selenium-deficient rats after 6 weeks were not very dramatic, in spite of the fact that glutathione peroxidase activity was undetectable. It would therefore appear that additional mechanisms are also involved in controlling the levels of lipid hydroperoxides in aorta.

Quality criteria for chromatographic analytical systems of polyunsaturated fatty acids metabolites

The most powerful technique for eicosanoids identification is gas chromatography prior to mass spectrometry. Results are highly dependent upon the choice of appropriate gas chromatographic systems ; the critical point of the system being the quality of the column. Our work is intended to provide a general overview of open tubular capillary columns which can be used for separation, identification and quantification of eicosanoids.

The conversion of dietary eicosapentaenoic acid to prostanoids and leukotrienes in man

Physiological and pathophysiological reactions like vascular resistance, thrombosis, wound healing, inflammation and allergy are modulated by oxygenated metabolites of arachidonic acid and related polyunsaturated fatty acids that are collectively termed eicosanoids. These compounds include prostaglandins, prostacyclin, thromboxane, leukotrienes and hydroxylated derivatives of arachidonic acid. The eicosanoids are all derived from essential fatty acids that must be provided in the diet, 4 and production of eicosanoids is controlled by cellular mechanisms for the uptake, release and oxygenation of the eicosanoid precursor fatty acids. Interference with eicosanoid synthesis is characteristic of many of the therapeutic agents in use in developed countries, including anti-inflammatory drugs and antithrombotic agents, antihypertensives and diuretics, suggesting that eicosanoids are involved in a broad spectrum of disease processes prevailing in these countries. A change of eicosanoid production and eicosanoid-dependent cellular functions may, however, also be achieved by altering eicosanoid precursor availability. Under our Western dietary conditions, arachidonic acid (AA; 20:4n6) is by far the dominant precursor fatty acid of biologically highly active eicosanoids of the two series. The major primary source of AA in our food chain is linoleic acid (18:2n6). At variance to the fatty acids of the linoleicor n 6-family in terrestrial animals and in most plant seeds---which are the major sources of our eicosanoid precursor fatty acids--the fatty acids of the linolenicor n 3-family predominate in green leaves and especially in marine lipidsY Here, eicosapentaenoic acid (EPA; 20:5n3) and docosahexaenoic acid (DHA; 22:6n3) are the major polyunsaturated fatty acids. Several independent lines of evidence suggest that changes in the natural history of hypertensive, atherothrombotic and inflammatory disorders may be achieved by altering the eicosanoid precursor availability. Native Greenland Eskimos 6 and also Japanese ~2 have a high dietary intake of long chain n 3 polyunsaturated fatty acids from seafood and a low incidence of myocardial infarction. Diets containing n 3 polyunsaturated fatty acids have also been found to reduce the severity of experimental cerebral 2 and myocardial S infarction, and retard autoimmune nephritis and prolong survival in NZB x NZW FI mice. m6 The eicosanoids derived from eicosapentaenoic acid have a spectrum of biological activity that is desirably different from that of the eicosanoids derived from arachidonic acid. However, until now, formation of eicosanoids from eicosapentaenoic acid has only been found in in vitro experiments.

Release of prostaglandins and monohydroxy and trihydroxy metabolites of linoleic and arachidonic acids by adult and fetal aortae and ductus arteriosus.

The conversion of arachidonic acid (20:4) to prostaglandins by vascular tissue is important in the adult because of the antithrombotic effect of prostacyclin and in the fetus because of the vasodilatory effect of prostaglandin (PG) E2 on the ductus arteriosus. We have shown that vascular tissue converts various polyunsaturated fatty acids to monohydroxy and trihydroxy metabolites derived from hydroperoxides, which may be involved in regulating prostaglandin synthesis. We have now measured the amounts of these hydroperoxide metabolites, as well as those of prostaglandins, released from slices of rat, rabbit and bovine aortae, as well as from fetal calf aorta and ductus arteriosus. The major oxygenated polyunsaturated fatty acid metabolite formed by rat and bovine blood vessels was 6-oxo-PGF1 alpha. Fetal calf aorta and ductus arteriosus produced about five times as much 6-oxo-PGF1 alpha as adult bovine aorta. Much smaller amounts of the cyclooxygenase products, PGE2, 12-hydroxy-5,8,10-heptadecatrienoic acid, 11-hydroxy-5,8,12,14-icosatetraenoic acid (11-hydroxy-20:4), and 15-hydroxy-20:4, were released by aortae. Small amounts of the lipoxygenase product, 12-hydroxy-20:4, were also detected. Substantial amounts of free and esterified monohydroxy and trihydroxy metabolites of linoleic acid (18:2) were detected, especially in rat and rabbit aortae. Rabbit aorta, which had low cyclooxygenase activity, formed more oxygenated 18:2 metabolites than 20:4 metabolites. Indomethacin did not inhibit the formation of the 18:2 metabolites, indicating that cyclooxygenase was not involved. Neither exogenous 13-hydroxy-18:2 nor trihydroxyoctadecenoic acid was incorporated to a large extent into lipids from vascular endothelial or smooth muscle cells, suggesting that the esterified 18:2 oxygenation products had arisen mainly via direct oxygenation of lipids.

Leukotrienes: Clinical significance

The leukotrienes, so named because of their initial identification in leukocyte preparations and the presence of three conjugated double bonds (a conjugated triene), are metabolites of the same polyunsaturated fatty acids (e.g., arachidonic acid) that give rise to the prostaglandins, thromboxanes, and several other families of biologically active lipids. Their potential clinical importance derives from their effects on vascular and other smooth muscle reactivity and on leukocyte function. Several leukotrienes may markedly influence the cellular and vascular responses that constitute an integral part of hypersensitivity and inflammatory reactions of the skin. Preliminary data from several laboratories have been presented that implicate a specific leukotriene in the evolution of the lesions of psoriasis.

Testosterone, prostate gland and hormone action

Although the androgens, testosterone (T) and its highly active metabolite dihydrotestosterone (DHT) play a role in the development and progression of prostate cancer, the mechanism(s) are unclear. Furthermore, 5α-reductase which catalyze the conversion of T to DHT, has been a target of manipulation in the treatment of prostatic cancer, hence synthetic 5α-reductase activity inhibitors have shown therapeutic promise. To demonstrate that nutrients derived from dietary sources can exert similar therapeutic promise, this study was designed using benign hyperplastic cells (BHC) and malignant tumorigenic cells (MTC) derived from Lobund–Wistar (L–W) rat model of prostatic adenocarcinoma to test the effects of gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA) and their 15-lipoxygenase metabolites on cellular 5α-reductase activity. Our data revealed: (i) that incubation of MTC with [3H]-T resulted in marked conversion to [3H]-DHT when compared to similar incubation with BHC; (ii) that DHT-enhanced activity of 5α-reductase was inhibited 80% by 15S-hydroxyeicosatrienoic acid, the 15-lipoxygenase metabolite of GLA, when compared to 55% by 15S-hydroxyeicosapentaenoic acid, the 15-lipoxygenase metabolite of EPA; and (iii) that their precursor fatty acids, respectively, exerted moderate inhibition. Taken together, the study underscores the biological importance of 15-lipoxygenase metabolites of polyunsaturated fatty acids (PUFAs) in androgen metabolism.