ADENOSINE-TRIPHOSPHATE PROTECTION OF CHLORDECONE-AMPLIFIED CCL4 HEPATOTOXICITY AND LETHALITY

Dietary exposure to a nontoxic level of chlordecone (10 ppm for 15 day s) followed by a single exposure to a subtoxic dose of CCl4 (100 mu l/ kg, ip) is known to result in a 67-fold amplification of CCl4 toxicity . The hypothesis that the underlying mechanism is due to incapacitatio n of hepatocytes leading to an ablation of the early-phase hermetic re sponse of tissue repair as a consequence of precipitous decline in hep atic glycogen and ATP, received experimental support from Mehendale in 1990. The present study was designed to investigate if direct adminis tration of ATP to rats maintained on the chlordecone diet would result in protection from the hepatotoxic and lethal effects of the chlordec one+CCl4 combination. Male Sprague-Dawley rats (125-150 g) were mainta ined either on a diet containing no added contaminants (control) or on a diet containing 10 ppm chlordecone for 15 days, and were challenged with CCl4 (100 mu l/kg, ip) on day 16. Without ATP administration all rats died within 72 h, while administration of ATP (100 mg/rat, sc) t o chlordecone-pretreated rats at -1, +1, 3, 5, 12, 24 and 36 h of CCl4 injection resulted in 100% survival. Injection of ATP, at -1, +1, 3 a nd 5 h of CCl4 administration to chlordecone pretreated rats decreased plasma enzyme elevations (alanine and aspartate aminotransferase, sor bitol dehydrogenase) as well as substantially preventing elevation of plasma bilirubin levels at 6, 12 and 24 h. Hepatic ATP levels were als o elevated at 6 and 12 h, but not at 24 h. Depletion of glycogen and s evere hypoglycemia was prevented by ATP administration throughout the time-course of the toxicity of chlordecone +CCl4 combination. To inves tigate the possibility of decreased metabolism of CCl4 during ATP prot ection, the in vivo metabolism of CCl4 was studied in rats undergoing chlordecone+CCl4 toxicity with or without ATP intervention. Regardless of ATP intervention, approximately 75% of the administered (CCl4)-C-1 4 was expired as unmetabolized CCl4 within 6 h in rats treated with th e chlordecone +CCl4 combination. However, the in vivo metabolism of (C Cl4)-C-14, as evidenced by (CO2)-C-14 expiration, was significantly in creased in chlordecone +CCl4-treated rats receiving ATP. An increase i n CCl4 metabolism instead of the anticipated decrease, indicates that the ATP protection cannot be attributed to diminished bioactivation of CCl4. These findings suggest that ATP administration during the early phase of injury leads to restored normal liver function and tissue-he aling mechanism, permitting restoration of hepatolobular structure and function and animal survival. (C) Journal of Hepatology.