Potentiation of brominated halomethane hepatotoxicity by chlordecone in the male rat

Abstract

The potentiation of hepatotoxicity by CCl 4 and a series of brominated analogs by chlordecone (CD) and phenobarbital (PB) pretreatment was investigated, using individually nontoxic levels of the halomethanes and the potentiating agents. Hepatotoxicity was determined by biochemical, functional, and histopathological parameters. Male Sprague-Dawley rats were maintained on a diet of 0 or 10 ppm CD or 225 ppm PB for 15 days. On Day 15, the animals were challenged with an approximately equimolar ip dose (10 μl/kg) of CCl 4, CCl 3Br, CBr 4, or CHBr 3 in corn oil. Twenty-four hours later, biliary excretion of phenolphthalein glucuronide (PG) and bile flow were determined in intact cannulated animals over a 60-min period. While biliary excretion of PG was significantly decreased by CD-CCl 3Br and PB-CBr 4 combinations, the former combination was not accompanied by decreased bile flow. Of the four halomethanes tested, CD significantly elevated serum transaminase (SGPT, SGOT) and isocitrate dehydrogenase (ICD) activities only for the CCl 3Br combination, while phenobarbital treatment was without effect. Histopathological examination indicated that livers from the CD-CCl 3Br combination alone displayed extensive centrilobular necrosis. Based on these features of hepatotoxicity, CD resulted in readily observable potentiation of CCl 3Br hepatotoxicity. The PB-CCl 3Br combination did not result in potentiated CCl 3Br hepatotoxicity at the dose level utilized in this study. These results emphasize the extremely powerful nature of the CD-CCl 3Br interaction.