Potentiation of BrCCl3 hepatotoxicity by chlordecone: biochemical and ultrastructural study.
Previous work has established that chlordecone (CD) potentiates the hepatotoxicity of BrCCl3. This interaction occurs at nontoxic levels of CD and BrCCl3. The present research was designed to investigate the mechanism governing the pathogenesis of potentiated hepatic injury and lethality induced by a low dose of BrCCl3 after dietary pretreatment with 10 ppm of CD for 15 days. On Day 16, a single dose of BrCCl3 (30 microliters/kg) was administered ip to rats maintained either on normal diet (ND) or on a diet contaminated with 10 ppm CD. Blood and liver samples were collected at 0, 3, 6, 12, 24, 36, and 48 hr after the halomethane administration for biochemical (ATP, bilirubin, glycogen) and for ultrastructural studies. A continuous increase in serum bilirubin and decrease in hepatic ATP and glycogen were observed in CD + BrCCl3 combination, indicating progressive injury, but not in other treatment groups. In ND + BrCCl3 combination, all biochemical indices were either normal or close to normal after 36 hr, suggesting complete recovery from hepatotoxicity. The most extensive ultrastructural changes characteristic of halomethane hepatotoxicity (necrosis, ballooned cells, and dilation of rough endoplasmic reticulum) were observed after the CD + BrCCl3 combination treatment. The progressive and early depletion of hepatic ATP and glycogen, and the progressive increase in toxicity along with decreased cell division in CD + BrCCl3-treated rats, indicate the association of compromised energy status and suppression of cell division and tissue repair in CD-potentiated BrCCl3 toxicity. These findings suggest that the suppression of stimulated hepatocellular regeneration results in the loss of the essential mechanism of tissue repair leading to continuation of the toxic liver injury associated with the CD + BrCCl3 combination treatment.
Faroon
O M
OM
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Henry
R W
RW
Soni
M G
MG
Mehendale
H M
HM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001975:Bromotrichloromethane / Q000633:toxicity*; D007631:Chlordecone / Q000633:toxicity*; D004357:Drug Synergism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains
D008112:Liver Glycogen; D000255:Adenosine Triphosphate; D001975:Bromotrichloromethane; D001663:Bilirubin; D007631:Chlordecone