Hepatic failure leads to lethality of chlordecone-amplified hepatotoxicity of carbon tetrachloride.
Chlordecone (Kepone) amplification of CCl4 toxicity occurs at small, nontoxic levels of chlordecone and CCl4 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 microliters/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 transaminase (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.(ABSTRACT TRUNCATED AT 250 WORDS)
Soni
M G
MG
Division of Pharmacology and Toxicology, Northeast Louisiana University, College of Pharmacy and Health Sciences, Monroe 71209-0470.
Mehendale
H M
HM
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism / Q000473:pathology*; D007631:Chlordecone / Q000633:toxicity*; D004796:Clinical Enzyme Tests; D007668:Kidney / Q000033:anatomy & histology; D017093:Liver Failure / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014166:Transferases / Q000378:metabolism
D010088:Oxidoreductases; D014166:Transferases; D007631:Chlordecone