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

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Abstract

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 β-oxidative and mi crosomal ω-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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalToxicological Sciences
Volume23
Issue number1
DOIs
StatePublished - Jul 1994
Externally publishedYes

Fingerprint

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

ASJC Scopus subject areas

  • Molecular Biology
  • Embryology
  • Cell Biology
  • Genetics
  • Developmental Biology
  • 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: Toxicological Sciences, Vol. 23, No. 1, 07.1994, p. 1-8.

Research output: Contribution to journalArticle

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