Protein expression analysis of drug-mediated hepatotoxicity in the Sprague-Dawley rat.
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.
Man
Wai J
WJ
Safety Assessment, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK. Wai_J_Man@gsk.com
White
Ian R
IR
Bryant
Duncan
D
Bugelski
Peter
P
Camilleri
Patrick
P
Cutler
Paul
P
Heald
Geoff
G
Lord
Peter G
PG
Wood
John
J
Kramer
Kerstin
K
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
D011506:Proteins; D017373:Cyproterone Acetate; D003907:Dexamethasone; D008701:Methapyrilene