Effects of chlordane pretreatment on the hepatotoxicity of carbon tetrachloride

Male albine rats weighing approximately 200 g received intraperitoneal injections of chlordane (25 mg/kg) in olive oil on each of three successive days. Controls included animals given only olive oil and untreated rats. Twenty-four hours after the last dose, augmented hepatic drug-metabolizing enzyme activity in chlordane-treated rats was reflected in vivo by a reduction in zoxazolamine-paralysis time and in vitro by an increased hepatic microsomal cytochrome P-450 level. The insecticide-treated animals did not, however, display any increase of hepatic microsomal NADPH-cytochrome c reductase activity. In chlordane-treated rats, electron microscopy revealed overt proliferation of smooth endoplasmic reticulum in the hepatocytes, particularly in those located in the central one-third to one-half of the liver lobules. Olive oil-treated controls showed no alterations in paralysis time, microsomal enzyme activity, or hepatocellular ultrastructure, when compared to the untreated animals. Identically prepared chlordane-treated and control rats then were challenged with an intraperitoneal injection of carbon tetrachloride (0.5 ml of a 25% solution of CCl₄ in olive oil). Some animals from each group were killed at 4 hr after the toxic challenge; and it was determined that, in each category, there was a sharp drop in hepatic microsomal cytochrome P-450 but no change in NADPH-cytochrome c reductase, as compared to prechallenge levels. The reduction in cytochrome P-450 was most striking in the insecticide-stimulated rats. The remaining animals from each CCl₄-injected group were sacrificed at 48 hr after the toxic challenge. Histologic slides prepared from their livers revealed more extensive hepatocellular necrosis in the chlordane-pretreated rats than was found in either the olive oil-pretreated rats or the animals with no treatment prior to CCl₄ administration. It was concluded that chlordane can induce smooth-membrane proliferation and can enhance drug-metabolizing enzyme systems in rat liver and that these changes are associated with an enhanced hepatotoxic response to CCl₄ administration. It was suggested that a sharp fall in hepatic microsomal cytochrome P-450 might serve as a relatively early indicator of toxic injury in an induced liver.