Abstract

Poly(ADP-ribose)polymerase (PARP) is a multifunctional nuclear enzyme, overactivation of which promotes inflammatory mediator expression and cell dysfunction. Acetaminophen (Tylenol) induces an acute liver toxicity followed by death via free radical and oxidant generation. We investigated whether a potent, novel inhibitor of PARP, INO-1001, can protect against acetaminophen induced liver damage. Treatment of male BALB/c mice with acetaminophen (350 mg/kg i.p.) results in 80% mortality at 24h. Simultaneous treatment with INO-1001 (10 or 30 mg/kg orally) reduced mortality to 10% and 0% respectively. Moreover, delaying the start of INO-1001 administration (10 or 30mg/kg orally) to 4h after acetaminophen administration still protects the mice reducing mortality to 15% and 30%, respectively. Analysis of serum and liver removed 8h after acetaminophen administration showed increased serum AST (from 132I14 to 2440I252 U/L) and liver MDA (from 1.9I0.1 to 4.4I0.3 nmol/mg protein). Simultaneous treatment with INO-1001 (10 or 30 mg/kg) decreased the serum AST to 572I88 and 438I78 U/L and the liver MDA to 2.2I0.4 and 2I0.2 nmol/mg protein respectively. In conclusion, PARP activation contributes to acetaminophen hepatotoxicity. References: 1.Virág L, Szabó C: The therapeutic potential of PARP inhibition. Pharmacological Reviews, 2002; 54: 375-429

Keywords: peroxynitrite, Liver, Hepatocytes, Acetaminophen