engleski

The role of prostaglandins in acute hepatotoxicity

It is known that Kupffer and other non-parenchymal liver cells are activated in hepatic injury, even if this is induced acutely by administration of high doses of hepatotoxic drugs. These cells secrete prostaglandins, proinflammatory cytokines and other products, which may contribute to pathogenic or repair processes. In these experiments we investigated the role of prostaglandin E2 (PGE2), prostaglandin I2 (PGI2) and thromboxane (TXA2) in acute liver toxicity induced in mice by Paracetamol (acetaminophen, AAP). Mice were given a lethal dose of AAP by gastric lavage and production of PGs was determined in supernatants of short term culture of livers slices, taken from mice at various times (2-24 hours) after AAP administration. Several agents which are known to have hepatoprotective effect and/or modulate PG synthesis (IL-1 , ketoconazole and dipyiridamole) were given to mice 1-2 hours before AAP. The synthesis of all prostanoids was greatly increased in liver slices of mice given AAP in comparison to mice given saline. Pretreatment of mice with IL-1 before administration of AAP further increased the synthesis of PGE2 and PGI2 and reduced the synthesis of TXA2 in liver slices. These changes in level of PG synthesis were significant at most time observed time intervals after AAP administration. The effect of ketoconazole and dipyridamole on PG synthesis was measured only at 6 hour interval after AAP administration. Both agents had similar effect as IL-1 , i.e., they increased the synthesis of PGE2 or PGI2 and reduced the synthesis of TXA2. All agents had a significant protective effect in vivo when given before AAP, i.e., they reduced the mortality of mice and level of serum aminotransferases in survived mice (ALT and AST). 16-16-dimethyl-PGE 2 (a stable analogue of (PGE 2 ) had a strong protective effect if given to mice before or up to two hours after AAP. These data suggest that PGE2 and PGI2 might have a protective and TXA2 noxious effect in acute liver injury.

prostaglandins; hepatotoxicity; acetaminophen; thromboxane

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