Attenuation of bromobenzene-induced hepatotoxicity by poly(ADP-ribose) polymerase inhibitors.

Abstract

Inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) have been demonstrated to attenuate pathophysiological conditions associated with toxicant-induced oxidative stress. This investigation evaluates Nicotinamide (NIC), a non-specific PARP inhibitor, and 6(5)-Phenanthridinone (Phen), a specific PARP-1 inhibitor, for their efficacy in blocking or attenuating bromobenzene (BB) induced hepatocellular toxicity. Male ICR mice were treated with an intraperitoneal injection of bromobenzene, followed by concomitant treatment with NIC or with NIC at 0.5, 1 and 2 hours after BB treatment, or with concomitant treatment of Phen at 10 mg/ml, 20 mg/ml, or 40 mg/ml solution concentration. Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3.5-fold increase in serum alanine transferase (ALT) compared to controls. Mice treated with 3 injections of NIC (at 0.5, 1 and 2 hours) after BB treatment demonstrated a 90% reduction in serum ALT at 24 hours after BB treatment (p < 0.05). Mice with concomitant BB and Phen treatment demonstrated a 75% reduction in ALT at 24 hours after treatment (p < 0.05). Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups. Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups. The PARP-1 inhibitors evaluated in this investigation produce clinically significant attenuation of BB-induced liver injury in male ICR mice.