Altered hepatic energy status in chlordecone (Kepone)-potentiated CCl4 hepatotoxicity.
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 CCl4 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 Mg2(+)-ATPase was altered significantly in rats maintained on diets contaminated with either CD (10 ppm), or phenobarbital (PB; 225 ppm) alone for 15 days. Similarly, CCl4 (100 microL/kg) administration alone did not alter hepatic ATP levels or mitochondrial Mg2(+)-ATPase activity in rats maintained on a normal diet. However, CCl4 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 Mg2(+)-ATPase was decreased significantly only starting at 6 hr (21%) after CCl4 administration, indicating that depletion of ATP at early time points was most likely due to rapid utilization consequent to toxic events. CCl4 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 CCl4 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 Mg2(+)-ATPase in CD + CCl4 treated rats indicate the association of compromised energy status with altered Ca2+ homeostasis, depletion of glycogen, and suppressed cell division in CD-potentiated CCl4 toxicity.
Kodavanti
P R
PR
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Kodavanti
U P
UP
Mehendale
H M
HM
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000032:analysis; D002251:Carbon Tetrachloride / Q000633:toxicity*; D007631:Chlordecone / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects*; D007306:Insecticides / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008917:Mirex / Q000633:toxicity; D010634:Phenobarbital / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains
D007306:Insecticides; D000255:Adenosine Triphosphate; D002251:Carbon Tetrachloride; D017301:Ca(2+) Mg(2+)-ATPase; D007631:Chlordecone; D010634:Phenobarbital; D008917:Mirex