phenanthrenes and Carbon-Tetrachloride-Poisoning

Carbon tetrachloride (CCl(4)) is routinely used as a model compound for eliciting centrilobular hepatotoxicity. It can be bioactivated to the trichloromethyl radical, which causes extensive lipid peroxidation and ultimately cell death by necrosis. Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) can rapidly reduce the levels of β-nicotinamide adenine dinucleotide and adenosine triphosphate and ultimately promote necrosis. The aim of this study was to determine whether inhibition of PARP-1 could decrease CCl(4)-induced hepatotoxicity, as measured by degree of poly(ADP-ribosyl)ation, serum levels of lactate dehydrogenase (LDH), lipid peroxidation, and oxidative DNA damage. For this purpose, male ICR mice were administered intraperitoneally a hepatotoxic dose of CCl(4) with or without 6(5H)-phenanthridinone, a potent inhibitor of PARP-1. Animals treated with CCl(4) exhibited extensive poly(ADP-ribosyl)ation in centrilobular hepatocytes, elevated serum levels of LDH, and increased lipid peroxidation. In contrast, animals treated concomitantly with CCl(4) and 6(5H)-phenanthridinone showed significantly lower levels of poly(ADP-ribosyl)ation, serum LDH, and lipid peroxidation. No changes were observed in the levels of oxidative DNA damage regardless of treatment. These results demonstrated that the hepatotoxicity of CCl(4) is dependent on the overactivation of PARP-1 and that inhibition of this enzyme attenuates the hepatotoxicity of CCl(4).

Topics: Animals; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Enzyme Inhibitors; Injections, Intraperitoneal; Liver; Male; Mice; Mice, Inbred ICR; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Structure-Activity Relationship

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in the detection of DNA strand termini. Extensive cellular damage can overactivate PARP-1, which rapidly depletes the cellular stores of NAD+ and ATP, resulting in necrotic cell death. The purpose of the present study was to determine whether 6(5H)-phenanthridinone, a potent inhibitor of PARP-1, could attenuate the hepatotoxicity of carbon tetrachloride (CCl4). Male ICR mice treated via the intraperitoneal route with CCl4 exhibited severe necrotic centrilobular lesions and significantly elevated serum transaminases. In contrast, the histopathology and serum biochemistry of animals treated concomitantly with CCl4 and 6(5H)-phenanthridinone were not significantly different versus controls. In conclusion, the results of this study demonstrate that the hepatotoxicity of CCl4 can be blocked independently of its metabolism and suggest the predominant role of PARP-1 overactivation in chemical-induced toxicity.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Carbon Tetrachloride Poisoning; Histocytochemistry; Male; Mice; Mice, Inbred ICR; Necrosis; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Protective Agents

To study the effect of tanshinone IIA on liver fibrosis in rats induced by CCl4.. Model of liver fibrosis in rats were induced by subcutaneous injection of CCl4 and malotilate was as positive control. The histological changes were observed with light microscope. The levels of ALT, AST, NO, HA, LN in serum and Hyp, MDA in liver tissue were determined to reveal the event liver damage.. Tanshinone IIA could significantly reduce the elevate levels of ALT, AST, NO, HA, LN in serum and Hyp, MDA in liver tissue. Pathological examination suggested tanshinone IIA has therapecuical effect on experimental liver fibrosis.. Tanshinone IIA may have therapeutical effect on CCL4-induced liver fibrosis in rats.

Topics: Abietanes; Animals; Antioxidants; Carbon Tetrachloride Poisoning; Drugs, Chinese Herbal; Female; Liver; Liver Cirrhosis, Experimental; Phenanthrenes; Rats; Rats, Sprague-Dawley

To study the effect of tanshinone IIA on two models of acute hepatic injury in mice.. Two acute hepatic injury models induced by carbon tetrachloride (CCl4) and D-galactosamine (D-GalN) in mice were used. ALT, AST in serum and MDA in liver homogenate were used as indexes.. Tanshinone IIA (10 mg.kg-1, 20 mg.kg-1, 30 mg.kg-1), similar to biophenyldicarboxylate, could decrease ALT, AST in serum and MDA in hepatic homogenate on acute hepatic injury induced by CCl4 and D-GalN.. Tanshinone IIA possessed obvious protective effect against liver injury induced by CCl4 or D-GalN.

Topics: Abietanes; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Male; Mice; Phenanthrenes; Phytotherapy