title: Toward the identification of liver toxicity markers: a proteome study in human cell culture and rats.
abstract: 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.
authors: Eurogentec Proteomics, Teltow/Berlin, Germany.
authors: Birgit
authors: B
authors: Thome-Kromer
authors: Ines
authors: I
authors: Bonk
authors: Mathias
authors: M
authors: Klatt
authors: Grit
authors: G
authors: Nebrich
authors: Marion
authors: M
authors: Taufmann
authors: Stewart
authors: S
authors: Bryant
authors: Ulrich
authors: U
authors: Wacker
authors: Andreas
authors: A
authors: Köpke
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000494:pharmacology / Q000633:toxicity; D000082:Acetaminophen / Q000494:pharmacology / Q000633:toxicity; D000429:Alcohol Oxidoreductases / Q000032:analysis; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000032:analysis; D002374:Catalase / Q000032:analysis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity; D030562:Databases, Protein; D004128:Dimethylnitrosamine / Q000494:pharmacology / Q000633:toxicity; D015180:Electrophoresis, Gel, Two-Dimensional; D006593:Hexokinase / Q000032:analysis; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology / Q000633:toxicity; D007526:Isoelectric Point; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008970:Molecular Weight; D020033:Protein Isoforms / Q000032:analysis; D011506:Proteins / Q000032:analysis; D020543:Proteome / Q000032:analysis / Q000187:drug effects*; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013752:Tetracycline / Q000494:pharmacology / Q000633:toxicity
chemical_list: D015415:Biomarkers; D020033:Protein Isoforms; D011506:Proteins; D020543:Proteome; D000082:Acetaminophen; D015058:1-Naphthylisothiocyanate; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D002374:Catalase; D006593:Hexokinase; D002222:Carbamoyl-Phosphate Synthase (Ammonia); D013752:Tetracycline; D004128:Dimethylnitrosamine; D002945:Cisplatin; D007213:Indomethacin