Effects of in Vivo Captan Administration on Cytotoxicity, Gluconeogenesis, ATP Levels, and Parameters Related to Oxidative Stress in Rat Liver

The aim of this study was to determine the effects of in vivo treatment with the fungicide captan on cytotoxicity and gluconeogenesis in isolated rat hepatocytes. In addition, the effects of the fungicide on lipid peroxidation and some antioxidant mechanisms were studied. Captan given by oral gavage to rats at a dose of 100 mg/kg was found to have an in vivo hepatotoxic effect, as indicated by the significant elevation in serum activities of aspartate aminotransferase and lactate dehydrogenase observed in fungicide-treated rats. In addition, a significant increase in the release into the incubation medium of these enzymes as well as the alanine aminotransferase was observed in vitro in hepatocyte suspensions from fungicide-treated rats. Hepatocytes isolated from captan-treated rats showed a significant inhibition in their ability to produce glucose in vitro from all the different gluconeogenic substrates studied: pyruvate (51.7%), lactate (30.1%), glycerol (38.8%), fructose (58.9%), and alanine (41.5%). Liver glucose-6-phosphatase, which catalyzes the final step of the gluconeogenesis pathway, was not altered by fungicide treatment. Similarly, no changes were observed in liver ATP levels in captan-treated rats in comparison to control animals. Captan treatment altered certain parameters related to oxidative stress. A significant increase in production of thiobarbituric acid reactants, which is an index of lipid peroxidation, was observed in the hepatocytes isolated from treated animals. No changes in liver oxygen consumption or in superoxide dismutase and glutathione-S-transferase were induced by captan administration. However, a significant decrease in certain antioxidant enzymes, such as glutathione peroxidase, catalase, and glutathione reductase, was observed in livers from rats treated with the fungicide. No alteration in hepatic total glutathione content, one of the major intracellular antioxidants, was observed in captan-treated animals. Histological studies revealed that captan-induced biochemical alterations were not accompanied by significant structural changes in the liver. Our results show, therefore, that the oral administration of captan has a hepatotoxic effect and causes an impairment of the gluconeogenic pathway of rat hepatocytes. The hepatotoxic effect seems to be related to the increase in hepatocyte lipid peroxidation induced by captan, which might be secondary, at least in part, to the inhibition of some antioxidants enzymes observed after the treatment with the fungicide. More study is necessary to suggest a possible connection between the failure of gluconeogenesis and the alterations of the prooxidant/antioxidant balance induced by the fungicide.