Excessive hepatic accumulation of intracellular Ca2+ in chlordecone potentiated CCl4 toxicity

Abstract

The possible role of Ca2+ in chlordecone potentiation of CCl4 hepatotoxicity was examined in male Sprague-Dawley rats. The rats were maintained on a diet containing either 0, 10, 25, 50 or 100 ppm chlordecone for 15 days. On day 15, they received a single i.p. injection of corn oil (1 ml/kg) or CCl4 (100 microliter/kg) in corn oil vehicle. The animals were killed at 1, 6, or 12 h after the oil or CCl4 challenge for hepatic Ca2+ determinations. Ca2+ in whole liver, mitochondria, microsomes or in cytosolic fraction was unaltered in any group of animals receiving chlordecone + oil treatments, indicating that chlordecone alone does not alter whole liver content or hepatic subcellular distribution of Ca2+, even after exposure to toxic levels (50 or 100 ppm). Administration of CCl4 at an otherwise non-toxic dose to chlordecone treated animals resulted in significant increases of whole liver and subcellular Ca2+ as compared to chlordecone alone and CCl4 alone with a characteristic biphasic response. These increases were significant at all 3 time points in whole liver, cytosolic and mitochondrial fractions. Microsomal Ca2+ increased only at 12 h after CCl4. The increases were all progressive with increases in dietary levels of chlordecone, indicating that chlordecone-induced sensitivity is responsible for CCl4 elicited perturbations in whole liver and intracellular Ca2+ levels. This study suggests that chlordecone modifies the liver plasma membrane to amplify the CCl4 elicited perturbations in hepatocellular Ca2+ homeostasis especially during 6-12 h after CCl4 administration. This perturbation of Ca2+ homeostasis may be related to the arrested repair and regeneration of damaged liver tissue leading to progressive deterioration observed in previous histomorphometric studies.