Modulation of Adriamycin-Induced Hepatotoxicity and Genotoxicity by Selective Inhibition of Phosphodiesterase-5 with Sildenafil in Wistar Rats

Abstract

This study investigated the effect of selective inhibition of phosphodiesterase-5 on hepatotoxicity and genotoxicity induced by adriamycin in rats. Thirty male Wistar rats (150 - 250 g) were randomly assigned into six groups of 5 rats/group. Negative, positive and sildenafil controls received physiological saline (10 ml/kg, p.o.), adriamycin (20 mg/kg, i.p.) and sildenafil (20 mg/kg, p.o.) respectively. Three separate groups were pretreated with sildenafil (5, 10 and 20 mg/kg respectively) prior to adriamycin injection. Adriamycin increased activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP). This was associated with degeneration and severe central venous congestion in hepatic cells and marked micronuclei formation in erythrocytes. Sildenafil (5 mg/kg) reduced AST and ALP activities by 18.7 % (p<0.001) and 14.1 % (p<0.01) respectively in the adriamycin-treated rats without any significant change in ALT and GGT activities even at 10 mg/kg. Although, sildenafil (20 mg/kg) raised GGT activity by 77.4% and 51.6% in normal and adriamycin-treated rats respectively, these effects were not significant when compared with control. Similarly, total protein and albumin did not change significantly across the various treatment groups. However, sildenafil significantly (p<0.05) increased glutathione levels at all doses and significantly reduced micronuclei formation by 65.5% and ameliorated morphological damage associated with adriamycin toxicity. Our data suggest that low doses of the phosphodiesterase-5 inhibitor, sildenafil, may protect against adriamycin-induced hepatotoxicity and genotoxicity.