Protective Effect of Gemfibrozil on Hepatotoxicity Induced by Acetaminophen in Mice: the Importance of Oxidative Stress Suppression

Abstract

Purpose: Gemfibrozil (GEM) apart from agonist activity at peroxisome proliferator-activated receptor-alpha (PPAR-α) has antioxidant and anti-inflammatory properties. Accordingly, the present study was designed to investigate the protective effect of GEM on acute liver toxicity induced by acetaminophen (APAP) in mice.Methods: In this study, mice divided in seven groups include, control group, APAP group, GEM group, three APAP groups pretreated with GEM at the doses of 25, 50 and 100 mg/kg respectively and APAP group pretreated with N-Acetyl cysteine. GEM, NAC or vehicle were administered for 10 days. In last day, GEM and NAC were gavaged 1 h before and 1 h after APAP injection. Twenty four hours after APAP, mice were sacrificed. Serum parameters include alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver tissue markers including catalase enzyme activity, reactive oxygen species (ROS), malondialdehyde and reduced glutathione (GSH) levels determined and histopathological parameters measured.Results: GEM led to significant decrease in serum ALT and AST activities and increase in catalase activity and hepatic GSH level and reduces malondialdehyde and ROS levels in the liver tissue. In confirmation, histopathological findings revealed that GEM decrease degeneration, vacuolation and necrosis of hepatocytes and infiltration of inflammatory cells.Conclusion: Present data demonstrated that GEM has antioxidant properties and can protect the liver from APAP toxicity, just in the same pathway that toxicity occurs by toxic ROS and that GEM may be an alternative therapeutic agent to NAC in APAP toxicity.

Acute acetaminophene-induced hepatotoxicity and nephrotoxicity; therapeutic effect of dexmedetomidine

“…NAC and DEX groups had statistically signifi cantly higher mean GSH-Px compared to the APAP group, while there were no significant differences identifi ed between NAC, DEX and NAC+DEX groups. CAT enzyme activity was signifi cantly reduced in the liver 24 hours after APAP administration and antioxidant treatment increased CAT activity (4). In our study, APAP administration caused a reduction in CAT levels, while administration of NAC alone caused a signifi cant increase in CAT levels.…”

“…Acetaminophen (APAP: N-acetyl-p-aminophenol, paracetamol) is an analgesic antipyretic medication that is commonly used globally (1,2,3). Therapeutic doses are safe, however toxic metabolites occurring during overdose cause severe organ toxicity (4). After oral intake a small portion of APAP (5-15 %) transforms into the toxic metabolite of N-acetyl-p-benzoquinoneimine (NAPQI).…”

“…NAPQI causes mitochondrial oxidative injury and increased reactive oxygen species (ROS) development (3,5,6). In overdose situations, NAPQI occurs at amounts that cannot be detoxifi ed and this causes toxicity (2,4). Currently, the best treatment known for APAP toxicity globally is N-acetylcysteine (NAC) treatment protocol (7,8).…”

“…It reduces mortality and morbidity if administered within the fi rst 8 hours (4,5,8). The worst clinical manifestation in APAP hepatotoxicity is fulminant liver failure.…”

“…Many molecules have been trialed with the aim of preventing injury in APAP toxicity. Some of these have antioxidant properties and there are studies showing benefi ts (2,4,6). Dexmedetomidine is a potent and specifi c α 2 receptor agonist with sedative, anxiolytic and analgesic effects.…”