15-Deoxy Prostaglandin J2 Enhances Allyl Alcohol-Induced Toxicity in Rat Hepatocytes

Abstract

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 D₂ (PGD₂) increases hepatocyte killing by allyl alcohol in vitro. In the present study the ability of the nonenzymatic product of PGD₂, 15-deoxy-Δ12,14-prostaglandin J₂ (15d-PGJ₂), to increase the cytotoxicity of allyl alcohol was evaluated. In a concentration-dependent manner, 15d-PGJ₂ significantly augmented cell death caused by allyl alcohol in isolated rat hepatocytes. 15d-PGJ₂ also increased the cytotoxicity of acrolein, the active metabolite of allyl alcohol. An agonist for the PGD₂ receptor neither reproduced the increase in allyl alcohol-mediated cytotoxicity nor altered the response to 15d-PGJ₂. Similarly, these responses were not affected by either an agonist or an antagonist for the peroxisome proliferator-activated receptor-γ. The enhancement by 15d-PGJ₂ of allyl alcohol-mediated cell killing was unaffected by augmentation or inhibition of cAMP. Protein synthesis was markedly decreased by 15d-PGJ₂, 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-κB), whereas at cytotoxic concentrations no translocation occurred. 15d-PGJ₂ inhibited translocation of NF-κB from the cytosol to the nucleus both in the presence and absence of allyl alcohol. Like 15d-PGJ₂, MG132, an inhibitor of NF-κB activation, enhanced allyl alcohol-induced hepatocyte death. Together these results indicate that 15d-PGJ₂ augments hepatocyte killing by allyl alcohol, and the mechanism may be related to the inhibition of NF-κB activation.