Assessment of the effects of pioglitazone, clofibrate and silymarin on acetaminophin induced liver injury

Abstract EN

Background Acetaminophen (N-acetyl-p-aminophenol, APAP) is a safe analgesic and antipyretic when dosed properly.

Overdoses of acetaminophen may cause toxic liver injury.

Protein acylation and free radical damage have been identified as pathways leading to hepatocyte damage. Aim : the aim of the present study was to investigate the hepatoprotective effect of clofibrate (CFB), peroxisome proliferators activated receptor a (PPAR a) agonists; pioglitazone, a PPARa agonist drug and silymarin (a polyphenol flavonoid) on acetaminophen induced liver injury in mice. Methods: Forty eight male Swiss mice divided into 4 main groups each of 12 mice and received daily treatment for 10 days.

Group I: received corn oil vehicle (2.5 ml/kg, ip).

Group II: treated with clofibrate (500 mg /kg, ip).

Group III: treated with pioglitazone (10 mg /kg, orally).

Group IV: treated with silymarin (50 mg / kg orally).

At the end of the treatment period, animals in each group were divided into 2 equal subgroups; controls and intoxicated.

Intoxicated mice were challenged with 400mg APAP / kg in 50% propylene glycol (PG) / water vehicle by gavage.

Control groups were challenged with PG vehicle only (5 ml / kg).

Mice were killed 24 h after challenge and plasma was separated for assessment of sorbitol dehydrogenase (SDH) activity as a biochemical indicator of APAP-induced hepatocellular necrosis.

The results of plasma SDH analysis were supported by histopathologically analysis of liver sections.

Liver samples obtained from mice were also used for determination of non-protein sulfhydryl's (NPSH) concentration as an indicator of hepatic reduced glutathione (GSH) content. Results: Liver injury was detected at 24 h after challenge with 400 mg APAP / kg as indicated by the increased sorbitol dehydrogenase (SDH) activity and the centrilobular necrosis detected in the liver histology in mice pretreated with corn oil vehicle.

In contrast, clofibrate (CFB) or silymarin-pretreated mice showed negligible levels of plasma SDH activity and nearly no change in liver histology when challenged with the same dose of APAP.

Pretreatment of mice with pioglitazone did not significantly protect the liver against acetaminophen induced damage.

The challenge of mice with 400 mg APAP/ kg resulted in significant depletion of NPSH in mice pretreated with corn oil in comparison to propylene glycol (PG)-challenged controls.

In CFB or silymarinpretreated mice NPSH concentrations did not significantly decrease after the administration of 400 mg APAP / kg.

In contrast, pretreatment with pioglitazone failed to protect the liver from NPSH Depletion. Conclusion : it may be concluded that pretreatment with clofibrate or silymarin, can protect against acetaminophen-induced hepatotoxicity.

The mechanism of this protection may involve, among other mechanisms, replenishing of the hepatic reduced glutathione stores.

On the other hand, pioglitazone, did not produce any hepatoprotection