Alpha-glutathione S-transferase in the assessment of hepatotoxicity--its diagnostic utility in comparison with other recognized markers in the Wistar Han rat.
The diagnostic utility of alpha-glutathione S-transferase (alphaGST) in the assessment of acute hepatotoxicity was compared with a range of markers including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Rats were given a single oral dose of either alpha-naphthylisothiocynate (AN IT), bromobenzene (BrB). or thioacetamide (TAM) at concentrations previously shown to induce marked hepatotoxicity. The progression of each hepatic lesion was monitored by the measurement of a battery of markers, including alphaGST, in plasma collected at time points ranging from 3 h to 7 days after dosing. alphaGST was seen to increase significantly at 24 h (ANIT/BrB) and 3 h (TAM) postdosing, corresponding with histopathological findings. For each compound, when the degree of insult was most severe, fold increases in alphaGST were greater than those seen with ALT and AST, yet lower than those seen with glutamate dehydrogenase (BrB and ANIT). sorbitol dehydrogenase (TAM), or total bilirubin and bile acids (ANIT). Elevations in alphaGST were also detected no earlier than any other marker. AlphaGST in the rat was shown to be a valid marker of hepatotoxicity; however, its measurement offered no additional information in detecting either the time of onset/recovery or the severity of each type of hepatic injury induced.
Giffen
Paul S
PS
Clinical Pathology, Cellular and Biochemical Toxicology, Safety Assessment, GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdom. psg21280@gsk.com
Pick
Chris R
CR
Price
Mark A
MA
Williams
Ann
A
York
Malcolm J
MJ
D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood / Q000737:chemistry; D000469:Alkaline Phosphatase / Q000097:blood / Q000737:chemistry; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000737:chemistry; D015415:Biomarkers / Q000097:blood / Q000737:chemistry; D001969:Bromobenzenes / Q000633:toxicity*; D005969:Glutamate Dehydrogenase / Q000097:blood / Q000737:chemistry; D005982:Glutathione Transferase / Q000187:drug effects* / Q000493:pharmacokinetics; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood / Q000737:chemistry; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000633:toxicity*; D014018:Tissue Distribution
D015415:Biomarkers; D001969:Bromobenzenes; D013853:Thioacetamide; D015058:1-Naphthylisothiocyanate; C032036:bromobenzene; D007064:L-Iditol 2-Dehydrogenase; D005969:Glutamate Dehydrogenase; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase