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The Role of Prostacyclin in Modifying Acute Hepatotoxicity of Acetaminophen in Mice

Prostaglandins (PGs) are lipid compounds that mediate variety of physiological and pathological functions in almost all body tissues and organs. Prostacyclin (prostaglandin I2, PGI2), which is synthesized by the vascular endothelium, is a potent vasodilator, inhibits the aggregation of platelets in vitro and has cytoprotective effect on gastrointestinal mucosa. The aim of this study was to determine whether PGI2 is playing a role in host defense to toxic effect of acetaminophen (APAP). This was investigated in C57Black/6 mice which were intoxicated with single lethal or high sublethal dose of APAP. APAP was administered to mice by gastric lavage and PGI2 agonists or antagonists were given intraperitoneally (i.p.) 30 minutes before or 2 hours after administration of APAP. The toxicity of APAP was determined by observing the survival of mice during 48 hours, by measuring the concentration of alanine-aminotransferase (ALT) in plasma 20-24 hours after APAP administration, and by liver histology. Mice were given either pure PGI2 (PGI2 sodium salt), its stable agonist (iloprost) or inhibitor of prostacyclin (IP)-receptor (CAY-10441). The results have shown that PGI2 exibits a strong hepatoprotective effect when it was given to mice either before or after APAP (both increase of survival of mice and decrease of plasma ALT levels were statistical significant). Iloprost has not shown a similar effect and CAY-10441 increased toxic effect of APAP if given 2 hours after its administration. Histopathological changes in liver generally support these findings. These investigations support the view that PGI2 is involved in defense of organism to noxious effects of xenobiotics on liver.

prostacyclin; acetaminophen; liver; toxicity; mice

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