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

Frank Witzmann, B. M. Jarnot, D. N. Parker, J. W. Clack

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Modification of Hepatic Immunoglobulin Heavy Chain Binding Protein (BiP/Grp78) Following Exposure to Structurally Diverse Peroxisome Proliferators. Witzmann, F. A., Parker, D. N., Jarnot, B. M., and Clack, J. W. (1994). Fundam. Appl. Toxicol. 23, 1-8. 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 homogenates. Perfluoro-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 β-oxidative and microsomal ω-oxidative enzymes. To clarify the mechanistic differences 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 analyzed using the Kepler 2D gel analysis system. Immunoglobulin heavy chain binding protein (BiP), also known as 78-kDa glucose-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 demonstrated. The nature of this PFDA-associated protein modification (reactive metabolite 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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalFundamental and Applied Toxicology
Volume23
Issue number1
DOIs
StatePublished - Jul 1994
Externally publishedYes

Fingerprint

Peroxisome Proliferators
Protein Binding
Carrier Proteins
Clofibrate
Liver
Gels
Proteins
Toxicity
Peroxisomes
Protein Folding
Electrophoresis, Gel, Two-Dimensional
Post Translational Protein Processing
Phosphorylation
Halothane
Metabolites
molecular chaperone GRP78
Electrophoresis
Rats
perfluorodecanoic acid
Enzymes

ASJC Scopus subject areas

  • Toxicology

Cite this

Modification of Hepatic Immunoglobulin Heavy Chain Binding Protein (BiP/Grp78) Following Exposure to Structurally Diverse Peroxisome Proliferators. / Witzmann, Frank; Jarnot, B. M.; Parker, D. N.; Clack, J. W.

In: Fundamental and Applied Toxicology, Vol. 23, No. 1, 07.1994, p. 1-8.

Research output: Contribution to journalArticle

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