Protection of chlordecone-potentiated carbon tetrachloride hepatotoxicity and lethality by partial hepatectomy.
Chlordecone (CD) pretreatment is known to markedly potentiate CCl4 hepatotoxicity. Previous studies have shown that prior exposure to CD obtunds the increased hepatocellular regeneration and repair observed in non-treated rats challenged with a single, low dose of CCl4. These observations allowed us to hypothesize that suppression of hepatic regeneration and tissue repair by CD + CCl4 combination treatment might be involved in this interaction. To test this hypothesis, CCl4 hepatotoxicity was evaluated in actively regenerating livers using CD-treated (10 ppm in the diet for 15 days), surgically partially hepatectomized (PH) male Sprague-Dawley rats. Rats undergoing no surgical manipulation (CTRL) and sham operation (SH) were included as appropriate controls. Surgical manipulations were conducted on day 15 of the dietary protocol. Based on liver-to-body weight ratios (LW/BW), mitotic indices, hepatic cytochrome P-450 content, and hepatic glutathione (GSH and GSSG) levels, PH-induced hepatocellular regeneration was not affected by pretreatment with CD. Thus, the PH model was considered valid for assessing the effects of CD + CCl4 combination treatment. CCl4 (100 microliter/kg; i.p.) was administered 1, 2, 4 or 7 days after the surgical manipulations. Hepatotoxicity was assessed 24 h later by measuring LW/BW and serum enzymes (SGPT, SGOT and ICD) in all four groups. Hepatic histopathological, histomorphometric and lethal effects were assessed in animals receiving CCl4 1 or 7 days after the surgical manipulations. CCl4-induced increases in LW/BW were observed in CD + PH rats receiving CCl4 4 or 7 days post-PH, but not in the 1 or 2 day post-PH groups in which the hepatocellular regeneration was maximal. CCl4-induced serum enzyme elevations were significantly less in the CD + PH rats as compared to CD + SH. This decrease in the serum enzyme elevations was most prominent in the 1 day post-PH group, where the hepatocellular mitotic activity was most pronounced. CCl4 lethality, assessed in the 1 day post-surgical manipulation group, was also decreased in the CD + PH rats in comparison to CD + SH rats. Such a protection was not observed in rats receiving CCl4 7 days post-PH. These data are consistent with and are supportive of the hypothesis that a suppression of otherwise normally stimulated hepatocellular regeneration following low-dose CCl4 administration is involved in the marked amplification of CCl4 toxicity by CD.
Bell
A N
AN
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216.
Young
R A
RA
Lockard
V G
VG
Mehendale
H M
HM
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology / Q000517:prevention & control*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007631:Chlordecone / Q000506:poisoning*; D003035:Cobalt / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D006498:Hepatectomy; D007306:Insecticides / Q000506:poisoning*; D008099:Liver / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008938:Mitosis / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D007306:Insecticides; D003035:Cobalt; D003577:Cytochrome P-450 Enzyme System; C018021:cobaltous chloride; D005978:Glutathione; D007631:Chlordecone