The role of prostaglandin E2 in acute acetaminophen hepatotoxicity in mice
Ivan Ćavar1, Tomislav Kelava2, Katarina Vukojević1,3, Mirna Saraga-Babić3 and Filip Čulo1,2
1Department of Physiology, School of Medicine, University of Mostar, Bosnia and Herzegovina, 2Department of Physiology, School of Medicine, University of Zagreb, Croatia and 3Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Croatia.
Offprint requests to: Ivan Ćavar, Department of Physiology, School of Medicine, University of Mostar, Bijeli brijeb b.b., 88000 Mostar, Bosnia and Herzegovina. e-mail: email@example.com
Summary. Prostaglandin E2 (PGE2), which is synthesized by many cell types, has a cytoprotective effect in the gastrointestinal tract and in several other tissues and cells. On the other hand, overdose or chronic use of a high dose of acetaminophen (Paracetamol, APAP) is a major cause of acute liver failure in the western world. These observations prompted us to investigate whether PGE2 plays a role in host defence to toxic effect of APAP. (CBAT6T6xC57Bl/6)F1 hybrid mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. Stabile analogue of PGE2, 16,16-dimethyl PGE2 (dmPGE2), or inhibitor of its production, CAY10526, were given intraperitoneally (i.p.) 30 minutes before or 2 hours after APAP administration. The toxicity of APAP was determined by observing the survival of mice during 48 hours, by measuring concentration of alanine-aminotransferase (ALT) in plasma 20-22 hours after APAP administration and by liver histology. The results have shown that PGE2 exhibits a strong hepatoprotective effect when it is given to mice either before or after APAP, while CAY10526 demonstrated mainly the opposite effect. Immunohistochemical or immunofluorescent examinations in the liver tissue generally support these findings, suggesting that PGE2 inhibited APAP-induced activation of nuclear factor kappa B (NF-κB). Similarly, PGE2 down regulated the activity of inducible nitric oxide synthase (iNOS), which was up regulated by APAP. Thus, by these and perhaps by other mechanisms, PGE2 contributes to the defence of the organism to noxious effects of xenobiotics on the liver. Histol Histopathol 25, 819-830 (2010)
Key words: Prostaglandin E2, Acetaminophen, Liver injury, NF-κB, Immunohistochemistry