Probucol and liver efficiency during chemically-induced hepatocarcinogenesis.
Probucol is a clinically used cholesterol-lowering drug, with pronounced antioxidant properties. The chemoprotective effect of probucol during the early steps of DENA and CCl4-induced hepatocarcinogenesis was studied. Treatment of animals with a single lethal dose of CCl4 (2ml/Kg, i.g.) after two weeks of DENA initiation, induced a significant increase in hepatic gamma-glutamyl transferase and liver content of glutathione and lipid peroxides five weeks later. On the other hand, a significant decrease in hepatic glutathione peroxidase activity was also observed after five weeks of CCl4 injection. Moreover, there was a significant decrease in hepatic blood flow manifested by decrease in indocyanine green elimination rate constant and increase in its half-life and area under the curve. The pharmacokinetic of antipyrine (a marker for hepatic metabolizing capacity) was altered due to decrease in the metabolizing capacity of damaged liver. In addition, haemorrhagic centrilobular necrosis and multifocal neoplastic lesions were microscopically detected. Treatment of animals with probucol (10 mg/Kg) three times/week for six weeks during DENA and CCl4-induced hepatocarcinogenesis counteracted significantly the alteration in hepatic blood flow and the hepatic metabolizing capacity. Moreover, probucol treatment restored the hepatic gamma-glutamyl transferase and liver content of glutathione and lipid peroxides. In addition, histopathological examination of liver specimens showed minimal centrilobular necrosis without any evidence of neoplastic lesions. The result of this study suggest that probucol may be useful as a chemopreventive agent, in addition to being a cholesterol-lowering drug with low toxicity.
el-Demerdash
Ebtehal
E
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Egypt.
el-Denshary
Ezz el-deen S
Eel-D
el-didi
Moneim
M
Al-Gharabli
Nagi
N
Osman
Abdel-Moneim M
AM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002251:Carbon Tetrachloride / Q000633:toxicity; D004052:Diethylnitrosamine / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D011341:Probucol / Q000494:pharmacology*; D051381:Rats; D005723:gamma-Glutamyltransferase / Q000097:blood
D016588:Anticarcinogenic Agents; D000924:Anticholesteremic Agents; D008054:Lipid Peroxides; D004052:Diethylnitrosamine; D002251:Carbon Tetrachloride; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D005978:Glutathione; D011341:Probucol