Accessible Requires Authentication Published by De Gruyter January 14, 2013

Modulation of paracetamol-induced hepatotoxicity by phosphodiesterase isozyme inhibition in rats: a preliminary study

Martins Ekor, Adesina O. Odewabi, Oluwafemi E. Kale, Titilayo O. Bamidele, Omolola A. Adesanoye and Ebenezer O. Farombi

Abstract

Background: Altered regulation of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) is present in liver cirrhosis. Several experimental studies have shown that selective modulation of NO metabolism in the liver reduces intrahepatic resistance and portal pressure in cirrhosis. This preliminary study investigated whether selective inhibition of phosphodiesterase-5 (PDE-5), which prevents the conversion of cGMP to 5′-GMP, as well as non-selective inhibition of PDE isozymes could ameliorate hepatic toxicity induced by paracetamol (PCM).

Methods: PCM (250 mg/kg, i.p.) was administered to induce hepatotoxicity. Control rats received physiological saline (10 mL/kg, p.o.), while sildenafil (a selective PDE-5 inhibitor) and aminophylline (a non-selective PDE inhibitor) were administered separately at 10 mg/kg p.o. to PCM-treated rats.

Results: PCM hepatotoxicity, characterized by elevation of aspartate and alanine aminotransferases, hepatic degeneration, and centrilobular necrosis, was attenuated by both PDE inhibitors. Sildenafil and aminophylline significantly (p<0.05) reduced plasma aspartate aminotransferase activity by 49.6% and 39.8%, respectively, with moderate increase in alanine aminotransferase activity by 26.1% and 20.4%, respectively, in PCM-treated rats. Decreases in total protein and albumin induced by PCM were significantly (p<0.05) prevented by 30.0% and 22.2%, respectively, following sildenafil administration, while aminophylline decreased these proteins by 14.0% and 25.9%, respectively. Sildenafil and aminophylline significantly (p<0.05) reduced lipid peroxidation by 30.7% and 19.7%, respectively, while moderately increasing glutathione (GSH) in the PCM-treated rats. Both drugs did not significantly alter the total cholesterol and triglyceride levels.

Conclusions: These preliminary data suggest that pharmacological inhibition of PDE isozymes may be a useful strategy in protecting against PCM hepatic toxicity.


Corresponding author: Dr. Martins Ekor, Department of Pharmacology, School of Medical Sciences, University of Cape Coast, Cape Coast, 233, Ghana, Phone: +2348062353814

Received: 2012-8-28
Accepted: 2012-11-24
Published Online: 2013-01-14
Published in Print: 2013-02-01

©2013 by Walter de Gruyter Berlin Boston