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ToxSci Advance Access published online on December 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh028
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received June 30, 2003; accepted October 14, 2003
© 2003 Society of Toxicology

Immunotoxicology

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

Jane F. Maddox 1*, Alison C. Domzalski 1, Robert A. Roth 1, and Patricia E. Ganey 1

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

* To whom correspondence should be addressed. E-mail: maddox{at}msu.edu.


  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 non-enzymatic product of PGD2, 15-deoxy-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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