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© 1994 Oxford University Press

research-article

Modification of Hepatic Immunoglobulin Heavy Chain Binding Protein (BiP/Grp78) Following Exposure to Structurally Diverse Peroxisome Proliferators

F. A. WITZMANN*, B. M. JARNOT{dagger}, D. N. PARKER* and J. W. CLACK*

*Molecular Anatomy Laboratory, Department of Biology, IUPUI-Columbus Columbus, Indiana {dagger}Toxicology Division, Armstrong Laboratory, Wright-Patterson AFB Ohio

Received August 9, 1993; accepted January 10, 1994

This investigation was conducted to determine the comparative effect of structurally diverse peroxisome proliferators (PP) on the two-dimensional protein pattern of rat liver whole ho mogenates. Perlluoro-n-decanoic acid (PFDA), perfluoro-n-octanoic acid (PFOA), clofibrate, and di(2-ethylhexyl)phthalate (DEHP) are all known to cause the proliferation of hepatic peroxisomes and the induction of peroxisomal ß-oxidative and mi crosomal {omega}-oxidative enzymes. To clarify the mechanistic dif ferences between these compounds with regard to the liver, we examined the unique patterns of protein alteration produced by in vivo exposure to them. Following exposure to various doses, whole liver homogenates were prepared and separated by two-dimensional gel electrophoresis (2DE) using the ISO-DALT system. Stained gels were digitized and protein patterns ana lyzed using the Kepler 2D gel analysis system. Immunoglobulin heavy chain binding protein (BiP), also known as 78-kDa glu cose-regulated protein (Grp78), was identified immunologically and by comigration of recombinant Grp78. BiP is a luminal endoplasmic reticular protein that functions in the assembly and folding of nascent proteins as they enter the ER. The present results suggest a selective posttranslational modification of BiP following PFDA exposure. Single-dose exposure to PFDA was associated with a notable charge modification of BiP that persists up to 30 days. PFOA, clofibrate, and DEHP had less effect in this regard. The identity of BiP/Grp78 as the halothane hepatitis-associated trifluoroacetylated protein was also demon strated. The nature of this PFDA-associated protein modifica tion (reactive metabol conjugation, abnormal ribosylation, or phosphorylation) is currently under investigation. These results document PFDA's unique toxicity as a PP and support the utility of 2D gel analysis in toxicity testing.


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