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ORIGINAL ARTICLE
Year : 2011  |  Volume : 1  |  Issue : 2  |  Page : 97-103

Hepatoprotective effects of select water-soluble PARP inhibitors in a carbon tetrachloride model


Department of Environmental and Occupational Health, Center for Environmental and Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL 33612, USA

Correspondence Address:
Raymond D Harbison
Department of Environmental and Occupational Health, Center for Environmental and Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL 33612
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2229-5151.84788

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Background: Inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARP-1) have been demonstrated to attenuate pathophysiologic conditions associated with oxidative stress, specifically with carbon tetrachloride (CT)-induced hepatotoxicity. Settings and Design: In this investigation, we evaluated 3 previously untested water-soluble PARP-1 inhibitors, namely, 3-aminobenzamide (ABA), 5-aminoisoquinolinone (AIQ), and N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide HCl (PJ-34) to determine their efficacy in blocking or attenuating CT-induced hepatotoxicity in male imprinting control region (ICR) mice. Statistical Analysis: Indicators of hepatotoxicity were compared with F-tests among groups to determine statistically significant effects. Pearson's correlation coefficients were used to evaluate the correlation between PARP inhibition and the attenuation of hepatotoxicity. Results and Conclusions: CT treatment resulted in hepatic cytotoxicity, increased serum transaminase (ALT), lipid peroxidation (MDA), intracellular glutathione (GSH) depletion, increased carbonyl content, and substantially increased PARP-1 activity. CT treatment also produced profound observable hemorrhagic necrosis in the hepatic centrilobular region of ICR mice. Pretreatment with PJ-34, ABA, and AIQ before CT treatment significantly decreased PARP-1 activity in hepatocytes after CT treatment by 3.4, 2.0, and 1.9 times, respectively. Corresponding to this reduction in PARP-1 activity, a significant reduction in the ALT levels and MDA and a reduction in the GSH depletion were observed. Also, there were no visible tissue defects in the liver samples from animals pretreated with individual PARP-1 inhibitors before CT administration. These results demonstrate the efficacy of the 3 previously untested water-soluble PARP-1 inhibitors in attenuating CT-induced hepatocellular toxicity and further characterize the role of PARP-1 activation and oxidative stress among the cascade of events in hepatocellular necrosis induced by CT treatment.


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