Biphasic effect of colchicine on acute liver injury induced by carbon tetrachloride or by dimethylnitrosamine in mice.
OBJECTIVE
The effects of colchicine on acute liver injury induced by carbon tetrachloride or by dimethylnitrosamine in mice were examined.


METHODS
Nonlethal acute liver injury was induced in male BALB/c mice by a single intraperitoneal injection of 0.8 ml/kg carbon tetrachloride or 15 mg/kg dimethylnitrosamine. 0.6 mg/kg colchicine was administered 18 h or 2 h intraperitoneally before hepatotoxin treatment.


RESULTS
Reversible centrilobular to mid-zone necrosis and apoptosis occupying half the liver lobular area was evoked by carbon tetrachloride, and dimethylnitrosamine, respectively. Administration of colchicine 18 h before hepatotoxins markedly suppressed liver injury, whereas colchicine administration 2 h before the hepatotoxins accelerated it. The hepatoprotective effect evoked by colchicine was due to reduction in liver cytochrome P450 content and P450 2E1 activity. In contrast, the hepatodestructive effect seen in the carbon tetrachloride model was related to the extent of lipid peroxidation promoting plasma membrane destruction, while the hepatodestructive effect in the dimethylnitrosamine model was due to suppression of Bcl-X(L) expression, leading to acceleration of apoptosis.


CONCLUSIONS
A biphasic effect of colchicine on carbon tetrachloride- and dimethylnitrosamine-induced acute liver injury was seen. The time interval between colchicine administration and the hepatotoxin treatment is crucial to the subsequent development of liver lesions.
Mizuoka
H
H
Department of Pathology II, Kansai Medical University, Moriguchi, Osaka, Japan.
Shikata
N
N
Yang
J
J
Takasu
M
M
Inoue
K
K
Tsubura
A
A
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D003078:Colchicine / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D008315:Malondialdehyde; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D004128:Dimethylnitrosamine; D003078:Colchicine