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Protective effect of cAMP on liver dammage by xenobiotics

INTRODUCTION. Previously we have shown that inflammatory cytokines (IL-1α /β and IL-6) have hepatoprotective effect if given to mice before administration of acetaminophen (APAP) or D-Galactozamine + LPS and that this effect is partially mediated by PGE2. Since many inflammatory cytokines stimulate the synthesis of cAMP as well as PGE2, we investigated the effect of agonists, antagonists and inhibitors of cAMP degradation on APAP toxicity. MATHERIALS AND METHODS. APAP (300 mg/kg) was administered by gastric lavage to mice which were given i.p., 1-2 hours before or up to 3 hours after a stable agonist (dibutyryl-cAMP – Db-cAMP) or antagonist (2, 3-dideoxyadenosine – DDA) of cAMP or inhibitor of phoshodiesterase IV (Rolipram). The survival of mice was followed for 72 hours and level of serum aminotransferases (AST and ALT) were determined 18-24 hours after administration of APAP. RESULTS. Db-cAMP (25 mg/kg) as well as Rolipram (8 mg/kg) significantly increased the survival of mice and reduced AST and ALT serum concentration if given 1-2 hours before or up to 2 hours after AAP administration. On the contrary, DDA (160 μ g/kg) decreased the survival of mice and increased serum aminotransferase concentration if given 2 hours before or ½ ; ; hours after APAP, but only effect on aminotransferase level was statistically significant. The treatment of animals with APAP greatly decreased the level of cAMP (20 or more times) in liver in vivo. IL-1β , which was previously shown to have protective effect on APAP toxicity, if given before APAP, greatly increased the synthesis of cAMP in liver in vivo in comparison to saline control (to approximately 2/3 of level in normal mice), and this effect could be blocked almost completely with DDA, given after IL-1α but before APAP. Similar results with Db-cAMP were obtained in mice intoxicated with D-galactosamine + lipopolysaccharide. Presently, we are investigating signaling ways of this protective effect, using more specific inhibitors of cAMP or its downstream intracellular mediators. Specially, we are investigating the role of NF-κ B and protein kinase A (PKA) in protective action of cAMP. CONCLUSIONS. cAMP has a significant protection on liver toxicity induced by xenobiotics.

c-AMP; Acetaminophen; hepatotoxicity; AST; ALT

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