3,3'-Selenobis(propionic acid).

In contrast to Se[CH(2)C(O)OH](2) versus S[CH(2)C(O)OH](2), the title compound, Se[CH(2)CH(2)C(O)OH](2) or C(6)H(10)O(4)Se, is structurally quite similar to its sulfur analogue. The molecule has twofold symmetry. The C-Se-C bond angle is 96.48 (8) degrees and the Se-C bond lengths are 1.9610 (14) A. The shortest Se.O intermolecular distance is 3.5410 (11) A. The O.O distances in the carboxylic acid dimers are 2.684 (2) A. The temperature dependence of the IR spectrum suggests tautomerism in the solid state.

Tetradecylthioacetic acid and tetradecylselenoacetic acid inhibit lipid peroxidation and interact with superoxide radical.

Reactive oxygen species are thought to induce cellular damage and to play a pathological role in several human diseases. Tetradecylthioacetic acid (TTA) was previously reported to prevent the oxidative modification of low-density lipoprotein (LDL) particles and to act as an antioxidant. In this study we present a new fatty acid analogue, namely tetradecylselenoacetic acid (TSA), in which the sulfur atom of TTA is replaced by a selenium atom. TSA was more potent than TTA in increasing the lag time before the onset of LDL oxidation and this effect was dose dependent. TTA and TSA were shown to reduce the iron-ascorbate-induced microsomal lipid peroxidation, TSA being more efficient than TTA. TTA and TSA, in the presence of iron, interacted with the superoxide radical as assessed by direct and indirect testing methods. TSA like TTA failed to scavenge 1.1-diphenyl-2-picrylhydrazyl radicals. TSA bound copper ions as shown by the wavelength spectra measurement. These results suggest that TTA and TSA exert their antioxidant capacity by interaction with copper or iron ions in radical scavenging, TSA being more potent than TTA. Nevertheless, a chelating effect resulting in chemically inactive metal ions cannot be excluded.

Tetradecylthioacetic acid inhibits the oxidative modification of low density lipoprotein and 8-hydroxydeoxyguanosine formation in vitro.

Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the formation of foam cells and in initiation and progression of atherosclerotic plaque. The hypolipidemic 3-thia fatty acids contain a sulfur atom and might therefore possess reducing (antioxidant) properties. Consequently, the effects of 3-thia fatty acids on the susceptibility of LDL particles to undergo oxidative modification in vitro were studied. Tetradecylthioacetic acid (TTA), incorporated into the LDL particle and increased the lag time of copper ion induced LDL oxidation in a dose-dependent manner, 80 mumol/L TTA reduced the generation of lipid peroxides during copper ion induced LDL oxidation (for 2 hours) by 100%, 2,2'-azobis-(2,4-dimethylvaleronitrile) induced LDL oxidation by 64%, and 2,2'-azobis-(2-amidinopropane hydrochloride) induced LDL oxidation (for 6 hours) by 21%. The electrophoretic mobility of the oxidized LDL was reduced by TTA in both copper ion and azo-compounds initiated oxidation. This fatty acid analogue was effectively able to reduce in a dose dependent manner the formation of 8-hydroxydeoxyguanosine from 2-deoxyguanosine with ascorbic acid as the radical producer. TTA bound copper(II) ions and did not reduce copper(II) to copper(I). It failed to scavenge the 1,1-diphenyl-2-picrylhydrazyl radicals. The results suggest that the modification of LDL in the lipid and protein moieties can be significantly reduced by TTA. This acid may exert its antioxidant effect partially through metal ion binding and through free radical scavenging.

Effect of 3-thia fatty acids on the lipid composition of rat liver, lipoproteins, and heart.

To investigate the importance of factors influencing the fatty acid composition, lipid and lipoprotein metabolism in the rat, the effect of 3-thia fatty acids of chain-length ranging from octyl- to hexadecylthioacetic acid were studied. In liver, very low density lipoprotein (VLDL), and low density lipoprotein (LDL), the hypolipidemic 3-thia fatty acids, namely C12-S-acetic acid to C14-S-acetic acid increased the amount of monoenes, especially oleic acid (18:ln-9). In contrast, the content of polyunsaturated fatty acids in liver, VLDL, and LDL decreased, mostly attributed to a reduction of eicosapentaenoic acid (EPA, 20:5n-3). Noteworthy, the hypolipidemic 3-thia fatty acids reduced the amount of arachidonic acid (AA, 20:4n-6) in LDL and HDL. 3-Thia fatty acids accumulated in the liver. In heart, as in liver, 3-thia fatty acids replaced fatty acids of chain-length homologues. In contrast to liver, we were unable to detect any changes in 18:ln-9. However, the n-3 polyunsaturated fatty acid content increased, particularly 20:5n-3 and docosahexaenoic acid (DHA, 22:6n-3) leading to an increased n-3/n-6 ratio. In conclusion, this study demonstrates that hypolipidemic 3-thia fatty acids change the fatty acid composition of organs and lipoproteins. These changes are linked to the expression and activity of hepatic delta9-desaturase, fatty acid oxidation, and displacement of normal fatty acids by 3-thia fatty acids. The fatty acid composition is regulated differently in liver and heart after administration of hypolipidemic 3-thia fatty acids.

Enhanced hepatic fatty acid oxidation and upregulated carnitine palmitoyltransferase II gene expression by methyl 3-thiaoctadeca-6,9,12,15-tetraenoate in rats.

This study reports the effects of a novel polyunsaturated 3-thia fatty acid, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on serum lipids and key enzymes in hepatic fatty acid metabolism compared to a saturated 3-thia fatty acid, tetradecylthioacetic acid. Palmitic acid treated rats served as controls. Fatty acids were administered by gavage in daily doses of 150 mg/kg body weight for 10 days. The aim of the present study was: (a) To investigate the effect of a polyunsaturated 3-thia fatty acid ester, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on plasma lipids in normolipidemic rats: (b) to verify whether the lipid-lowering effect could be consistent with enhanced fatty acid oxidation: and (c) to study whether decreased activity of esterifying enzymes and diversion to phospholipid synthesis is a concerted mechanism in limiting the availability of free fatty acid as a substrate for hepatic triglyceride formation. Repeated administration of the polyunsaturated 3-thia fatty acid ester for 10 days resulted in a reduction of plasma triglycerides (40%), cholesterol (33%) and phospholipids (20%) compared to controls. Administration of polyunsaturated and saturated 3-thia fatty acids (daily doses of 150 mg/kg body weight) reduced levels of lipids to a similar extent and followed about the same time-course. Both mitochondrial and peroxisomal fatty acid oxidation increased (1.4-fold- and 4.2-fold, respectively) and significantly increased activities of carnitine palmitoyltransferase (CPT) (1.6-fold), 2,4-dienoyl-CoA reductase (1.2-fold) and fatty acyl-CoA oxidase (3.0-fold) were observed in polyunsaturated 3-thia fatty acid treated animals. This was accompanied by increased CPT-II mRNA (1.7-fold). 2,4-dienoyl-CoA reductase mRNA (2.9-fold) and fatty acyl-CoA oxidase mRNA (1.7-fold). Compared to controls, the hepatic triglyceride biosynthesis was retarded as indicated by a decrease in liver triglyceride content (40%). The activities of glycerophosphate acyltransferase, acyl-CoA: 1,2-diacylglycerol acyltransferase and CTP:phosphocholine cytidylyltransferase were increased. The cholesterol lowering effect was accompanied by a reduction in HMG-CoA reductase activity (80%) and acyl-CoA:cholesterol acyltransferase activity (33%). In hepatocytes treated with methyl 3-thiaoctadeca-6,9,12,15-tetraenoate, fatty acid oxidation was increased 1.8-fold compared to controls. The results suggest that treatment with methyl 3-thiaoctadeca-6,9,12,15-tetraenoate reduces plasma triglycerides by a decrease in the availability of fatty acid substrate for triglyceride biosynthesis via enhanced fatty acid oxidation, most likely attributed to the mitochondrial fatty acid oxidation. It is hypothesized that decreased phosphatidate phosphohydrolase activity may be an additive mechanism which contribute whereby 3-thia fatty acids reduce triglyceride formation in the liver. The cholesterol-lowering effect of the polyunsaturated 3-thia fatty acid ester may be due to changes in cholesterol/cholesterol ester synthesis as 60% of this acid was observed in the hepatic cholesterol ester fraction.

Comparative effects of oxygen and sulfur-substituted fatty acids on serum lipids and mitochondrial and peroxisomal fatty acid oxidation in rat.

Feeding tetradecyloxyacetic acid (a 3-oxa fatty acid) to rats led to decreased serum cholesterol and decreased serum triacylglycerol, resembling the effects of the corresponding 3-thia fatty acid (tetradecylthioacetic acid). The 3-oxa fatty acid inhibited strongly the mitochondrial fatty acid oxidation and led to the development of fatty liver, while the 3-thia fatty acid stimulated the mitochondrial fatty acid oxidation. Feeding tetradecyloxypropionic acid (a 4-oxa fatty acid) had less effect on the serum lipids. It stimulated fatty acid oxidation in the mitochondria and lowered the hepatic level of triacylglycerol. The corresponding 4-thia fatty acid (tetradecylthiopropionic acid) inhibited mitochondrial fatty acid oxidation and induced development of fatty liver. All these compounds, both the oxa and the thia fatty acids, induced some increase in the activity of the peroxisomal acyl-CoA oxidase. Repeated administration of 3-oxadicarboxylic acid to rats resulted in no lipid lowering effects, and marginal changes of fatty acyl-CoA oxidase activity. Oxidation of the S-atom of the 3-thia fatty acid to the corresponding sulfoxide or sulfone eliminated the metabolic effects of the thia fatty acid. The study has shown that the effects of 3- and 4-oxa fatty acids are in some ways opposite to those of the 3- and 4-thia fatty acids. The possibility that the lipophilicity of the fatty acid analogues may be an important factor behind the differences observed are discussed. It is suggested that these oxa- and thia-analogues of fatty acids may be useful in studies on the regulation of fatty acid metabolism.