Carbon tetrachloride-induced alterations of hepatic calmodulin and free calcium levels in rats pretreated with chlordecone.
Calmodulin, a low molecular weight Ca2+ binding protein, regulates a large number of cell activities including cell division. Previous studies from our laboratory indicated excessive accumulation of Ca2+ in hepatocytes succeeded by rapid glycogen breakdown and suppressed cell division in rats receiving CCl4 after previous dietary exposure to 10 ppm chlordecone. Since calmodulin plays a major role in Ca2(+)-regulated events and has been reported to be localized in mitotic apparatus during cell division, we have assessed subcellular distribution of calmodulin and estimated cytosolic phosphorylase a to indicate cytosolic free Ca2+ levels in livers of rats fed 0 ppm or 10 ppm (chlordecone) in the diet for 15 days before CCl4 (100 microliters/kg) administration to understand the role of Ca2(+)-calmodulin in chlordecone + CCl4 toxicity. Hepatotoxicity was assessed by determining serum AST and ALT succeeded by histopathological observations of liver sections. Serum aminotransferases were significantly elevated 6 hr after CCl4 administration to normal rats and returned to control level by 24 hr. However, serum AST and ALT elevations were severalfold higher, and progressive increase was observed starting 4 hr after CCl4 administration to chlordecone rats. Histopathological observations of liver sections for necrotic, swollen and lipid-laden cells provided findings commensurate with the serum enzyme data. These data indicate that normal rats do recover from CCl4 hepatotoxicity. However, the CCl4 hepatotoxicity is progressive in chlordecone rats without recovery. In normal rats, CCl4 administration resulted in a slight increase in phosphorylase a starting at 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
Kodavanti
P R
PR
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216.
Kodavanti
U P
UP
Mehendale
H M
HM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000494:pharmacology / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D007631:Chlordecone / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004357:Drug Synergism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008297:Male; D010762:Phosphorylase a / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism
D002147:Calmodulin; D002251:Carbon Tetrachloride; D000242:Cyclic AMP; D010762:Phosphorylase a; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007631:Chlordecone; D002118:Calcium