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ToxSci Advance Access originally published online on December 2, 2003
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Toxicological Sciences 77, 290-298 (2004)
Copyright © 2004 by the Society of Toxicology

IMMUNOTOXICOLOGY

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

Jane F. Maddox1, Alison C. Domzalski, Robert A. Roth and Patricia E. Ganey

Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824

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-{Delta}12,14-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-{gamma}. 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-{kappa}B), whereas at cytotoxic concentrations no translocation occurred. 15d-PGJ2 inhibited translocation of NF-{kappa}B from the cytosol to the nucleus both in the presence and absence of allyl alcohol. Like 15d-PGJ2, MG132, an inhibitor of NF-{kappa}B 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-{kappa}B activation.

Key Words: acrolein; hepatocytotoxicity; NF-{kappa}B; PPAR{gamma}; prostaglandin.


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