© 1993 Oxford University Press
research-article |
Hepatic Failure Leads of Lethality of Chlordecone-Amplified Hepatotoxicity of Carbon Tetrachloride1
Division of Pharmacology and Toxicology, Northeast Louisiana University, College of Pharmacy and Health Sciences Monroe, Louisiana 71209–0470
Received December 28, 1992; accepted July 6, 1993
Hepatic Failure Leads to Lethality of Chlordecone-Amplified Hepatotoxicity of Carbon Tetrachloride. SONI, M. G., AND MEHENDALE, H. M. (1993). Fundam. Appl. Toxicol. 21, 442–450.
Chlordecone (Kepone) amplification of CCl4 toxicity occurs at small, nontoxic levels of chlordecone and CC14 and results in highly increased irreversible hepatotoxicity culminating in lethality. Although it is generally assumed that CCl4 lethality is due to hepatic failure, no definitive studies are available in the literature bridging massive liver failure and death. The present studies were designed to evaluate whether hepatic failure is the cause of the lethality during chlordecone-amplified CCl4 toxicity. Male Sprague-Dawley rats were maintained on control or a chlordecone (10 ppm) diet for 15 days and injected with CCl4 (100 µl/kg, ip) on Day 16. Rats were killed at 0, 6, 12, 24, 36, and 48 hr after CCl4 challenge. Hepatic failure was evaluated by measuring plasma glucose, ammonia, bilirubin, aspartate trans-aminase (AST), alanine transaminase (ALT), sorbitol dehydrogenase (SDH), hepatic ATP, glycogen, and by histological and histomorphometric analyses. Plasma creatinine, urea, and kidney histopathology were also assessed for possible renal injury. As expected CCl4 administration to chlordecone-pretreated rats resulted in 20% lethality by 36 hr, which progressed with time, and all rats died within 72 hr. A significant and progressive hypoglycemia was observed with a 60% reduction in plasma glucose at 48 hr. Hepatic glycogen content dropped precipitously. Similarly, hepatic ATP levels remained suppressed (80% of control) at all the time points studied. Plasma ammonia levels were significantly elevated, and by 48 hr, a threefold increase was observed. Plasma ALT, AST, SDH, and bilirubin increased progressively until the death of rats receiving the chlordecone + CCl4 combination. Histopathologically, the liver sections revealed a progressive and irreversible damage evidenced by vacuolation, accumulation of fat, and increase in hepatocellular necrosis resulting in disrupted hepatolobular structure. Administration of the same dose of CCl4 to rats maintained on a normal diet resulted in only marginal changes in plasma enzymes, no increase in serum bilirubin, and no significant injury in liver sections at 24 hr. CCl4 administration to chlordecone-pretreated rats resulted in a marginal increase in plasma creatinine and urea only at later time points. Histopathological examination of sections of kidneys from rats receiving either chlordecone + CCl4 combination or the same dose of CCl4 alone did not reveal any evidence of significant renal injury. The clinical end points of hepatic function measured in the present study are consistent with the sequel of hepatic failure and hepatic encephalopathy leading to animal death in chlordecone-amplified CCl4 toxicity.