Altered hepatic energy status in chlordecone (kepone®)-potentiated ccl 4 hepatotoxicity

Abstract

Previous studies have demonstrated that increased intracellular calcium, depletion of glycogen, and suppressed hepatocellular division resulting in progression of hepatic lesion without recovery are associated with chlordecone (CD)-potentiated CCl 4 hepatotoxicity. Since these phenomena are indicative of compromised hepatic energy status, the present studies were designed to investigate this possibility. Neither hepatic ATP content nor mitochondrial Mg 2+-ATPase was altered significantly in rats maintained on diets contaminated with either CD (10 ppm), mirex (10 ppm) or phenobarbital (PB; 225 ppm) alone for 15 days. Similarly, CCl 4 (100 μL/kg) administration alone did not alter hepatic ATP levels or mitochondrial Mg 2+-ATPase activity in rats maintained on a normal diet. However, CCl 4 administration to CD pretreated rats resulted in significantly decreased hepatic ATP content as early as 1 hr (36%), and this decrease was irreversibly progressive with time (81% at 6 hr). Oligomycin-sensitive Mg 2+-ATPase was decreased significantly only starting at 6 hr (21%) after CCl 4 administration, indicating that depletion of ATP at early time points was most likely due to rapid utilization consequent to toxic events. CCl 4 administration to mirex or PB pretreated rats resulted in a smaller decrease in ATP levels (18–24%) only at 24 hr, returning to normal levels by 36–48 hr, in accord with rapid recovery from limited liver injury. These findings indicate that CCl 4 administration to CD but not to PB or mirex pretreated rats results in a severely compromised energy status of the liver. The progressive and early depletion of liver ATP and the inhibition of Mg 2+-ATPase in CD + CCl 4 treated rats indicate the association of compromised energy status with altered Ca 2+ homeostasis, depletion of glycogen, and suppressed cell division in CD-potentiated CCl 4 toxicity.