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)