title: Protein expression analysis of drug-mediated hepatotoxicity in the Sprague-Dawley rat.
abstract: This study has investigated the protein changes in rat liver elicited by a group of model hepatotoxicants, methapyrilene, cyproterone acetate and dexamethasone and offers a compelling argument in support of the use of two-dimensional polyacrylamide gel electrophoresis and mass spectrometry for the identification of compound specific biomarkers. The different treatments caused distinct changes to the rat liver proteome. Many of the protein changes could be associated with the known pharmacological and toxicological mechanisms of action of these drugs, whereas for other proteins, the rationale behind the alterations was less obvious. Furthermore, these changes can be used to classify the treatments with a view to utilising them as 'molecular signatures' to further our understanding of less well studied drugs such as SKF-106686 (an adrenoreceptor agonist). This approach has the potential for opening up new avenues for the exploration of molecular mechanisms of toxicity. This paper has explored the feasibility of proteomics to provide valuable information on the biochemical consequences elicited by hepatototoxic drugs.
authors.affiliation: Safety Assessment, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK. Wai_J_Man@gsk.com
authors.forename: Wai J
authors.initials: WJ
authors.lastname: Man
authors.forename: Ian R
authors.initials: IR
authors.lastname: White
authors.forename: Duncan
authors.initials: D
authors.lastname: Bryant
authors.forename: Peter
authors.initials: P
authors.lastname: Bugelski
authors.forename: Patrick
authors.initials: P
authors.lastname: Camilleri
authors.forename: Paul
authors.initials: P
authors.lastname: Cutler
authors.forename: Geoff
authors.initials: G
authors.lastname: Heald
authors.forename: Peter G
authors.initials: PG
authors.lastname: Lord
authors.forename: John
authors.initials: J
authors.lastname: Wood
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kramer
mesh_terms: D000818:Animals; D017373:Cyproterone Acetate / Q000633:toxicity*; D003907:Dexamethasone / Q000633:toxicity*; D015180:Electrophoresis, Gel, Two-Dimensional; D004591:Electrophoresis, Polyacrylamide Gel; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008701:Methapyrilene / Q000633:toxicity*; D014176:Protein Biosynthesis; D011506:Proteins / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D011506:Proteins; D017373:Cyproterone Acetate; D003907:Dexamethasone; D008701:Methapyrilene