Toward the identification of liver toxicity markers: A proteome study in human cell culture and rats

The effects of toxic and nontoxic compound treatments were investigated by high resolution custom developed 2–11 pH gradient NEPHGE (non equilibrium pH gradient electrophoresis) two‐dimensional electrophoresis. Two models were compared: (i) in vivo rat and (ii) the human cell line HepG2, to test the...

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Bibliographic Details
Published in:Proteomics (Weinheim) 2003-10, Vol.3 (10), p.1835-1862
Main Authors: Thome-Kromer, Birgit, Bonk, Ines, Klatt, Mathias, Nebrich, Grit, Taufmann, Marion, Bryant, Stewart, Wacker, Ulrich, Köpke, Andreas
Format: Article
Language:English
Subjects:
1-Naphthylisothiocyanate - pharmacology
1-Naphthylisothiocyanate - toxicity
Acetaminophen - pharmacology
Acetaminophen - toxicity
Alcohol Oxidoreductases - analysis
Aldehyde Reductase
Aldo-Keto Reductases
Animals
Biomarkers - analysis
Carbamoyl-Phosphate Synthase (Ammonia) - analysis
Catalase - analysis
Cell Line, Tumor
Cisplatin - pharmacology
Cisplatin - toxicity
Databases, Protein
Dimethylnitrosamine - pharmacology
Dimethylnitrosamine - toxicity
Electrophoresis, Gel, Two-Dimensional
HepG2 proteome
Hexokinase - analysis
Humans
Indomethacin - pharmacology
Indomethacin - toxicity
Isoelectric Point
Liver - chemistry
Liver - drug effects
Liver - pathology
Male
Matrix-assisted laser desorption/ionization-mass spectrometry protein identification
Molecular Weight
Nonequilibrium pH gradient electrophoresis
Nonequilibrium pH gradient gel electrophoresis
Predictive toxicology
Protein Isoforms - analysis
Proteins - analysis
Proteome - analysis
Proteome - drug effects
Proteomics
Rat liver proteome
Rats
Rats, Sprague-Dawley
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Tetracycline - pharmacology
Tetracycline - toxicity
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Summary:The effects of toxic and nontoxic compound treatments were investigated by high resolution custom developed 2–11 pH gradient NEPHGE (non equilibrium pH gradient electrophoresis) two‐dimensional electrophoresis. Two models were compared: (i) in vivo rat and (ii) the human cell line HepG2, to test their suitability in a proteomics based approach to identify a toxicity marker. 163 and 321 proteins were identified from the rat liver and the HepG2 proteome. These represent various isoforms of 113 and 194 different NCBI annotated gene sequences, respectively. Nine compounds were selected to induce proteome variations associated with liver toxicity and metabolism. The rat liver proteome database consists of 78 gels, the HepG2 database of 52 gels. Variant proteins were assessed regarding their usefulness as a toxicity marker by evaluating their treatment specificity against multiple control treatments. Thirteen potential toxicity marker proteins were found in rat liver and eight in HepG2. Catalase and carbamoylphosphate synthetase‐1 isoforms were found to be significantly changed after treatment by 4/4 and 3/4 toxic compounds in rat liver, respectively. Aldo‐keto‐reductase family 1, member C1 was implicated for 3/4 liver cell toxic compounds in HepG2. Our approach was able to differentiate the quality of potential toxicity markers and provided useful information for an ongoing characterization of more compounds in a wider number of toxicity classes.
ISSN:1615-9853
1615-9861
DOI:10.1002/pmic.200300552