Upon chemical, radiation-induced or enzymatic oxidation, cis-polyunsaturated fatty acids, i.e., C18:2(n-6), C18:3(n-3), C20:2(n-6), C20:3(n-6), C20:3(n-3), C20:4(n-6), C20:5(n-3), C22:2(n-3), ...C22:4(n-6), C22:6(n-3), were found to generate saturated short and medium-chain length dicarboxylic acids, which can be regarded as a distinctive feature of the particular double bonds positions in the polyunsaturated fatty acid molecule. Two different dicarboxylic acids, which were unambiguously quantified by GC-MS, were produced from a single fatty acid: one deriving from the oxidative splitting at the level of the first double bond in the molecule, the other being two-carbon-atoms lower homologous. Formation of dicarboxylic acids occurred also from triacylglycerols and phospholipids containing cis-polyunsaturated fatty acids. In this case, following oxidation, the diacids remained covalently bound to the starting molecule and transesterification was necessary for identification. Being extremely stable and easily detectable compounds, dicarboxylic acids may be considered potential markers of oxidative attack to both free and esterified unsaturated fatty acids.
Azelaic acid is an aliphatic dicarboxylic acid (HOOC-(CH2)7-COOH) which has recently been shown to have some practical therapeutic applications in skin diseases of different etiologies. It possesses ...diverse biological activities and its mechanisms of action are still under investigation. Azelaic acid, as disodium salt (C(9)2Na), at concentrations from 0.05 mM to 1.0 mM is capable of inhibiting significantly the hydroxylation of 1-tyrosine to 1-DOPA due to hydroxylradicals (HO.) produced by Fenton reaction. Similarly C(9)2Na significantly inhibits the heterogeneous photocatalytic oxidation of toluene to cresols, and the peroxidation of arachidonic acid (C20:4,n6), due to HO. formed by dissolved oxygen in the presence of UV-irradiated semiconductor TiO2 (photo-Fenton type reaction). C(9)2Na decomposition and its by-products formation are quantifiable only at high HO. concentrations. On the contrary, C(9)2Na is not a scavenger of O2-. generated by xanthine-xanthine oxidase system. Under the same experimental conditions, mannitol behaves like C(9)2Na. These data indicate that HO. scavenging capacity of C(9)2Na in vitro, and represent a useful tool for further investigations on the mechanisms of action of azelaic acid in biological systems.
We have previously shown that azelaic acid, a C9 dicarboxylic acid, as disodium salt (C(9)2Na) is capable of inhibiting significantly the hydroxylation of aromatic compounds and the peroxidation of ...arachidonic acid due to reactive hydroxyl radicals (HO.). In this paper we have investigated the ability of C(9)2Na to inhibit the oxyradical induced toxicity towards two tumoral cell lines (Raji and IRE1) and normal human fibroblasts (HF). Oxyradicals were generated either by the addition of polyphenols to the medium, or by direct irradiation of phosphate buffered-saline in which cells were incubated from 15 min prior to incubation in normal medium. The effects of C(9)2Na were compared with those obtained by mannitol (MAN), superoxide dismutase (SOD) and catalase (CAT). C(9)2Na, MAN, SOD and CAT significantly decreased the polyphenol toxicity towards cell lines cultured up to 24 h. After 48 h of incubation the above compounds lost the capability of protecting cells from polyphenol toxicity. This suggests that the toxic role of oxyradicals (O2-., H2O2, HO.) persists for about 24 h and, subsequently other toxic mechanisms must be involved, which are not affected by oxyradical scavengers. SOD and CAT did not show any protective effect on UV induced cytotoxicity, while both C(9)2Na and MAN were capable of reducing significantly the UV damage towards cell lines, even after 48 h incubation. This can be explained by the fact that UV cytotoxicity depends mainly on the generation of HO., that can be "scavenged" by C(9)2Na or MAN, but not by SOD or CAT. C(9)2Na and MAN were not significantly degraded in the period during which they afford protection against HO..
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