PARP-1 Inhibitor Attenuates Cocaine-Induced Hepatotoxicity

Abstract

Cocaine abuse is associated with multiple health problems including occasional hepatic failure and death. The mechanism of cocaine-induced hepatotoxicity (CIH) is not clear, although studies in mice have demonstrated that cocaine-induced liver injury may be mediated by nitric oxide and reactive oxygen species. Recently, we have found that cocaine increases poly (ADP-ribose) polymerase (PARP) activity in the liver. Therefore, inhibition of PARP may block CIH. A preliminary assessment of the PARP inhibitor 3,4-Dihydro-5-(4-(1-piperidinyl)butoxyl)-1(2H)-isoquinolinone (DPQ) in ICR mice failed to attenuate CIH. However, the PARP inhibitor 1,5-dihydroxyisoquinoline (DIQ) successfully attenuated CIH. Mean ALT activity of 569 IU caused by cocaine treatment alone, was limited to 79 IU in ICR mice concomitantly treated with DIQ (10 mg/kg, ip). The protective effect of DIQ was also associated with prevention of development of lipid peroxidation in liver tissue, reduced depletion of glutathione (GSH), and a reduced production of nitrites. Cocaine-induced TBARS was significantly decreased by DIQ from a mean of 5.7 nmol/mg protein to a mean of 2.5 nmol/mg protein, similar to untreated mice. Hepatic GSH was reduced more than 2 fold following cocaine administration but treatment with DIQ conserved GSH at the level of untreated mice. The protective effect of DIQ in attenuating CIH can potentially be explained by the dual inhibitory effect of DIQ that reduces induction of PARP and inducible nitric oxide synthetase (iNOS). The DIQ attenuation of CIH provides evidence for a PARP and iNOS modulated mechanism of action for this hepatocellular pathology.