Hepatoprotective effects of 6(5H)-phenanthridinone from chemical-induced centrilobular necrosis.
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.
Banasik
Marek
M
Center for Environmental and Occupational Risk Analysis and Management, Department of Environmental and Occupational Health, College of Public Health, University of South Florida, Tampa, Florida 33612, USA.
Stedeford
Todd
T
Ueda
Kunihiro
K
Muro-Cacho
Carlos
C
Su
Phi-Huynh
PH
Tanaka
Seigo
S
Harbison
Raymond D
RD
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D002252:Carbon Tetrachloride Poisoning / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006651:Histocytochemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents / Q000494:pharmacology*
D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents; C040601:phenanthridone; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase