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      Heme Metabolism and Lipid Peroxidation in Rat Kidney Hexachlorobenzene–Induced Porphyria: A Compartmentalized Study of Biochemical Pathogenic Mechanisms

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          In the present study, the effects of hexachlorobenzene (HCB) on lipid peroxidation and heme metabolism in the different constitutive suborgans of the kidney were determined. For this purpose, conjugated diene and malondialdehyde levels, as lipid peroxidation parameters, and porphyrin accumulation, uroporphyrinogen decarboxylase activity, and its inhibitor formation, as measures of heme metabolism, were determined in renal cortex, medulla, and papilla. Adult Wistar rats were treated with HCB during 1, 2, 3, or 4 weeks. A significant increase in cortical conjugated dienes was observed from the 1st week of treatment. The malondialdehyde levels rose by 47, 34, and 28% after 2, 3, and 4 weeks of intoxication, respectively. The porphyrin content showed a tenfold increase after 4 weeks of treatment, and the uroporphyrinogen decarboxylase activity was reduced by 26 and 58% with respect to control values after 3 and 4 weeks of treatment, respectively. The results demonstrate a direct correlation between the oxidative environment and the effect elicited by the drug on heme metabolism in the renal cortex. In contrast, in papilla and medulla, where the antioxidant systems were higher, HCB showed no porphyrinogenic effect.

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          Studies on the active centre of rat liver porphyrinogen carboxylyase in vivo effect of hexachlorobenzene

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            Oxidation of uroporphyrinogens by hydroxyl radicals Evidence for nonporphyrin products as potential inhibitors of uroporphyrinogen decar☐ylase

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              Urinary porphyrins as biological indicators of oxidative stress in the kidney

              Reduced porphyrins (hexahydroporphyrins, porphyrinogens) are readily oxidized in vitro by free radicals which are known to mediate oxidative stress in tissue cells. To determine if increased urinary porphyrin concentrations may reflect oxidative stress to the kidney in vivo, we measured the urinary porphyrin content of rats treated with mercury as methyl mercury hydroxide (MMH) or cephaloridine, both nephrotoxic, oxidative stress-inducing agents. Rats exposed to MMH at 5 ppm in the drinking water for 4 weeks showed a 4-fold increase in 24-hr total urinary porphyrin content and a 1.3-fold increase in urinary malondialdehyde (MDA), an established measure of oxidative stress in vivo. Treatment with cephaloridine alone (10-500 mg/kg, i.p.) produced a dose-related increase in urinary MDA and total porphyrin levels up to 1.6 and 7 times control values, respectively. Injection of MMH-treated rats with cephaloridine (500 mg/kg) caused a synergistic (20-fold) increase in urinary porphyrin levels, but an additive (1.9-fold) increase in the MDA concentration. Studies in vitro demonstrated that cephaloridine stimulated the iron-catalyzed H2O2-dependent oxidation of porphyrinogens to porphyrins in the absence of either microsomes or mitochondria. Additionally, porphyrinogens were oxidized to porphyrins in an iron-dependent microsomal lipid peroxidation system. Moreover, porphyrinogens served as an effective antioxidant (EC50 approximately 1-2 microM) to lipid peroxidation. These results demonstrate that MMH and cephaloridine synergistically, as well as individually, promote increased oxidation of reduced porphyrins in the kidney and that this action may be mechanistically linked to oxidative stress elicited by these chemicals. Increased urinary porphyrin levels may, therefore, represent a sensitive indicator of oxidative stress in the kidney in vivo.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                15 October 1999
                : 23
                : 1
                : 20-26
                aDepartamento de Ciencias Biológicas, Cátedra de Biología Celular e Histología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, IQUIFIB–CONICET, y bDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
                25950 Kidney Blood Press Res 2000;23:20–26
                © 1999 S. Karger AG, Basel

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                Figures: 3, Tables: 2, References: 22, Pages: 7
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