| 14657518 |
Maddox JF, Domzalski AC, Roth RA, Ganey PE: 15-deoxy prostaglandin J2 enhances allyl alcohol-induced toxicity in rat hepatocytes. Toxicol Sci. 2004 Feb;77(2):290-8. Epub 2003 Dec 2.
Allyl alcohol causes hepatotoxicity that is potentiated by small doses of bacterial lipopolysaccharide (LPS) through a cyclooxygenase-2 (COX-2)-dependent mechanism. The COX-2 product prostaglandin D (2) (PGD (2)) increases hepatocyte killing by allyl alcohol in vitro. In the present study the ability of the nonenzymatic product of PGD (2), 15-deoxy-Delta12,14-prostaglandin J (2) (15d-PGJ (2)), to increase the cytotoxicity of allyl alcohol was evaluated. In a concentration-dependent manner, 15d-PGJ (2) significantly augmented cell death caused by allyl alcohol in isolated rat hepatocytes. 15d-PGJ (2) also increased the cytotoxicity of acrolein, the active metabolite of allyl alcohol. An agonist for the PGD (2) receptor neither reproduced the increase in allyl alcohol-mediated cytotoxicity nor altered the response to 15d-PGJ (2). Similarly, these responses were not affected by either an agonist or an antagonist for the peroxisome proliferator-activated receptor-gamma. The enhancement by 15d-PGJ (2) of allyl alcohol-mediated cell killing was unaffected by augmentation or inhibition of cAMP. Protein synthesis was markedly decreased by 15d-PGJ (2), but inhibition of protein synthesis alone with cycloheximide did not increase allyl alcohol-mediated cell killing. Allyl alcohol at subtoxic concentrations increased translocation of nuclear factor kappa B (NF-kappaB), whereas at cytotoxic concentrations no translocation occurred. 15d-PGJ (2) inhibited translocation of NF-kappaB from the cytosol to the nucleus both in the presence and absence of allyl alcohol. Like 15d-PGJ (2), MG132, an inhibitor of NF-kappaB activation, enhanced allyl alcohol-induced hepatocyte death. Together these results indicate that 15d-PGJ (2) augments hepatocyte killing by allyl alcohol, and the mechanism may be related to the inhibition of NF-kappaB activation. |
31(0,1,1,1) |