title: Modulation of paracetamol-induced hepatotoxicity by phosphodiesterase isozyme inhibition in rats: a preliminary study.
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.
authors: Department of Paharmacology, Olabisi Onabanjo University, Sagamu, Nigeria. m.ekor@uccsms.edu.gh
authors: Martins
authors: M
authors: Ekor
authors: Adesina O
authors: AO
authors: Odewabi
authors: Oluwafemi E
authors: OE
authors: Kale
authors: Titilayo O
authors: TO
authors: Bamidele
authors: Omolola A
authors: OA
authors: Adesanoye
authors: Ebenezer O
authors: EO
authors: Farombi
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D000628:Aminophylline / Q000494:pharmacology*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000628:Aminophylline; D000082:Acetaminophen; D000068677:Sildenafil Citrate; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione