linoleic-acid and ferric-nitrilotriacetate

The activity of a single IP administration (15 or 30 mg/Kg body weight) of vanillyl nonanoate, a simplified analog of capsiate, on ferric nitrilotriacetate (Fe-NTA)-mediated oxidative damage was investigated. A sub-lethal dose of Fe-NTA (15 mg Fe/Kg body weight) was administered IP to rats; animals were sacrificed, and kidney and plasma were collected 1 h after injection. In response to the Fe-NTA administration, a reduction of the levels of total lipids, total unsaturated fatty acids and cholesterol was observed, accompanied by a rise in the concentrations of malondialdehyde (MDA), conjugated dienes fatty acids hydroperoxides and 7-ketocholesterol in plasma and kidney 1 h after administration. A pre-treatment with synthetic capsiate (SCPT) showed remarkable protective effect on the reduction of the levels of total lipids, total unsaturated fatty acids and cholesterol, and the cellular antioxidant vitamin E, inhibiting the increase of MDA, conjugated dienes fatty acids hydroperoxides and 7-ketocholesterol in the plasma and kidney. The protective effect of SCPT and two analogues (vanillyl alcohol and vanillin) during the linoleic acid and cholesterol oxidation was investigated in in vitro systems, providing evidence of definite structure-activity relationships.

Topics: Analysis of Variance; Animals; Antioxidants; Body Weight; Capsaicin; Cholesterol; Chromatography, High Pressure Liquid; Fatty Acids; Ferric Compounds; Hydrogen Peroxide; Ketocholesterols; Kidney; Linoleic Acid; Lipid Peroxidation; Lipids; Malondialdehyde; Models, Chemical; Models, Statistical; Mutagens; Nitrilotriacetic Acid; Oxidative Stress; Oxygen; Rats; Rats, Wistar; Structure-Activity Relationship; Time Factors; Vanillic Acid

This study examined the generation of reactive oxygen species (ROS) and the induction of lipid peroxidation by carcinogenic iron(III)-NTA complex (1:1), which has three conformations with two pKa values (pKa1 approximately 4, pKa2 approximately 8). These conformations are type (a) in acidic conditions of pH 1-6, type (n) in neutral conditions of pH 3-9, and type (b) in basic conditions of pH 7-10. The iron(III)-NTA complex was reduced to iron(II) complex under cool-white fluorescent light without the presence of any reducer. The reduction rates of three species of iron(III)-NTA were in the order type (a) >> type (n) > type (b). Iron(III)-NTA-dependent lipid peroxidation was induced in the presence and absence of preformed lipid peroxides (L-OOH) through processes associated with and without photoreduction of iron(III). The order of the abilities of the three species of iron(III)-NTA to initiate the three mechanisms of lipid peroxidation was: (1) type (a) > type (n) > type (b) in lipid peroxidation that is induced L-OOH- and H2O2-dependently and mediated by the photoreduction of iron(III); (2) type (b) > type (n) > type (a) in lipid peroxidation that is induced L-OOH- and H2O2-dependently but not mediated by the photoreduction of iron(III); (3) type (n) > type (b) > type (a) in lipid peroxidation that is induced peroxide-independently and mediated by the photoactivation but not by the photoreduction of iron(III). The rate of lipid peroxidation induced L-OOH-dependently is faster than that induced H2O2-dependently in the mechanism (1), but the rate of lipid peroxidation induced H2O2-dependently is faster than that induced L-OOH-dependently in the mechanism (2). In the lag process of mechanism (3), L-OOH and/or some free radical species, not 1O2, were generated by photoactivation of iron(III)-NTA. These multiple pro-oxidant properties that depend on the species of iron(III)-NTA were postulated to be a principal cause of its carcinogenicity.

Topics: alpha-Tocopherol; Antioxidants; beta Carotene; Carcinogens; Ferric Compounds; Hydrogen Peroxide; Hydrogen-Ion Concentration; Linoleic Acid; Lipid Peroxidation; Lipid Peroxides; Micelles; Molecular Conformation; Nitrilotriacetic Acid; Oxidation-Reduction; Photochemistry; Ultraviolet Rays

A certain iron chelate, ferric nitrilotriacetate (Fe3+-NTA) is nephrotoxic and also carcinogenic to the kidney in mice and rats, a distinguishing feature not shared by other iron chelates tested so far. Iron-promoted lipid peroxidation is thought to be responsible for the initial events. We examined its ability to initiate lipid peroxidation in vitro in comparison with that of other ferric chelates. Chelation of Fe2+ by nitrilotriacetate (NTA) enhanced the autoxidation of Fe2+. In the presence of Fe2+-NTA, lipid peroxidation occurred as measured by the formation of conjugated diene in detergent-dispersed linoleate micelles, and by the formation of thiobarbituric acid-reactive substances in the liposomes of rat liver microsomal lipids. Addition of ascorbic acid to Fe3+-NTA solution promoted dose-dependent consumption of dissolved oxygen, which indicates temporary reduction of iron. On reduction, Fe3+-NTA initiated lipid peroxidation both in the linoleate micelles and in the liposomes. Fe3+-NTA also initiated NADPH-dependent lipid peroxidation in rat liver microsomes. Although other chelators used (deferoxamine, EDTA, diethylenetriaminepentaacetic acid, ADP) enhanced autoxidation, reduction by ascorbic acid, or in vitro lipid peroxidation of linoleate micelles or liposomal lipids, NTA was the sole chelator that enhanced all the reactions.

Topics: Adenosine Diphosphate; Animals; Ascorbic Acid; Deferoxamine; Edetic Acid; Ferric Compounds; Iron Chelating Agents; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Liposomes; Membrane Lipids; Micelles; Microsomes, Liver; NADP; Nitrilotriacetic Acid; Oxidation-Reduction; Oxygen; Pentetic Acid; Rats; Rats, Inbred Strains