A proteomic analysis of thioacetamide-induced hepatotoxicity and cirrhosis in rat livers.
Thioacetamide (TAA) administration is an established technique for generating rat models of liver fibrosis and cirrhosis. Oxidative stress is believed to be involved as TAA-induced liver fibrosis is initiated by thioacetamide S-oxide, which is derived from the biotransformation of TAA by the microsomal flavine-adenine dinucleotide (FAD)-containing monooxygense (FMO) and cytochrome P450 systems. A two-dimensional gel electrophoresis-mass spectrometry approach was applied to analyze the protein profiles of livers of rats administered with sublethal doses of TAA for 3, 6 and 10 weeks respectively. With this approach, 59 protein spots whose expression levels changed significantly upon TAA administration were identified, including three novel proteins. These proteins were then sorted according to their common biochemical properties and functions, so that pathways involved in the pathogenesis of rat liver fibrosis due to TAA-induced toxicity could be elucidated. As a result, it was found that TAA-administration down-regulated the enzymes of the primary metabolic pathways such as fatty acid beta-oxidation, branched chain amino acids and methionine breakdown. This phenomenon is suggestive of the depletion of succinyl-CoA which affects heme and iron metabolism. Up-regulated proteins, on the other hand, are related to oxidative stress and lipid peroxidation. Finally, these proteomics data and the data obtained from the scientific literature were integrated into an "overview model" for TAA-induced liver cirrhosis. This model could now serve as a useful resource for researchers working in the same area.
Low
Teck Yew
TY
Department of Biochemistry, Faculty of Medicine, National University of Singapore, Singapore.
Leow
Chon Kar
CK
Salto-Tellez
Manuel
M
Chung
Maxey C M
MC
D000818:Animals; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D005293:Ferritins / Q000737:chemistry; D005355:Fibrosis; D005978:Glutathione / Q000378:metabolism; D006418:Heme / Q000737:chemistry; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced*; D008715:Methionine / Q000378:metabolism; D018384:Oxidative Stress; D010105:Oxygenases / Q000737:chemistry; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013853:Thioacetamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity*; D013997:Time Factors; D014357:Trypsin / Q000494:pharmacology; D015854:Up-Regulation
D005227:Fatty Acids; D013853:Thioacetamide; C029188:thioacetamide-S-oxide; D006418:Heme; D005293:Ferritins; D008715:Methionine; D007501:Iron; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D014357:Trypsin; D005978:Glutathione