title: 6,(5H)-phenanthridinone protects against carbon tetrachloride-induced cytotoxicity in human HepG2 cells.
abstract: Carbon tetrachloride (CCl4) is a compound associated with free radical mediated hepatotoxicity in humans and laboratory animals. Previous research indicates that the cytotoxicity caused by CCl4 may be mediated by the rapid induction of PARP-1, a nuclear repair enzyme, which results in celluar depletion of NAD+ and ATP. Animal models indicate that the inhibition of PARP-1 after CCl4 exposure will attenuate cytotoxicity in mouse hepatocytes. In this investigation, the potential hepatoprotective effects of the PARP-1 inhibitor 6,(5H)-phenanthridinone against CCl4-induced hepatotoxicity was tested in human cells from the HepG2 primary hepatoma cell line. Cytotoxicity assay results indicate significant reductions in cell death with treatment of 20uM and 40uM solutions of 6,(5H)-phenanthridinone. PARP-1 activity assay results confirm that these protective effects correspond to the inhibition of PARP-1 by 6,(5H)-phenanthridinone. The findings in this study indicate that the effect of PARP-1 inhibition on cytotoxicity in human hepatocytes after CCl4 insult is consistent with the effect of PARP-1 inhibition on cytotoxicity found in animal models.
authors.affiliation: Center for Environmental/Occupational Risk Analysis and Management, University of South Florida, Tampa, FL, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Grivas
authors.forename: Seigo
authors.initials: S
authors.lastname: Tanaka
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ueda
authors.forename: Giffe
authors.initials: G
authors.lastname: Johnson
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Harbison
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C040601:phenanthridone; D002251:Carbon Tetrachloride; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1