CCl4-induced lipoperoxidation triggers a lethal defect in the liver plasma membranes.
Loss of calcium regulation across the plasma membrane of hepatocytes is responsible for irreversible cell damage by CCl4. The mode of action of colchicine in CCl4 acute liver damage is not completely understood. We followed the time courses of the changes in lipoperoxidation, the activities of liver plasma membrane Ca2(+)-ATPase, gamma-glutamyl transpeptidase and alkaline phosphatase, as well as the time courses of serum markers of liver damage in rats acutely intoxicated with CCl4. We assessed the effects of colchicine in this model and evaluated the effect of this drug on liver cytochrome P-450. Increased lipoperoxidation is the earliest and shortest lasting effect of CCl4 in the liver and is followed by a decrease in the activities of plasma membrane-bound enzymes. The alterations in serum enzymes showed a slower onset and were more protracted. Colchicine pretreatment produced a small decrease in cytochrome P-450 in the liver but completely prevented most of the changes produced by CCl4 in lipoperoxidation, liver plasma membrane enzyme activities and serum enzyme activities. We conclude that CCl4 metabolites trigger lipoperoxidation and then produce a longer lasting change in the plasma membrane, which thus allows calcium accumulation. Colchicine prevents the early mechanisms of CCl4 damage, and its effect on cytochrome P-450 perhaps plays only a contributory role.
Mourelle
M
M
Pharmacology and Toxicology Department, CINVESTAV-IPN, México.
Meza
M A
MA
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D056486:Chemical and Drug Induced Liver Injury; D003078:Colchicine / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects*; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000252:Calcium-Transporting ATPases; D003078:Colchicine