15-deoxy prostaglandin J2 enhances allyl alcohol-induced toxicity in rat hepatocytes.
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.
Maddox
Jane F
JF
Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824, USA. maddox@msu.edu
Domzalski
Alison C
AC
Roth
Robert A
RA
Ganey
Patricia E
PE
D000171:Acrolein / Q000633:toxicity; D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D004357:Drug Synergism; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020005:Propanols / Q000633:toxicity*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
C477819:15-deoxyprostaglandin J2; D016328:NF-kappa B; D020005:Propanols; C006463:allyl alcohol; D000171:Acrolein; D000410:Alanine Transaminase; D015230:Prostaglandin D2