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Toxicologic Pathology
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Alpha-Glutathione S-Transferase in the Assessment of Hepatotoxicity—Its Diagnostic Utility in Comparison with Other Recognized Markers in the Wistar Han Rat

Paul S. Giffen

Clinical Pathology, Cellular and Biochemical Toxicology, Safety Assessment, GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdom, psg21280@ gsk.com

Chris R. Pick

Department of Pathology, Preclinical Safety Sciences, GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdom

Mark A. Price

Department of Toxicology, Preclinical Safety Sciences, GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdom

Ann Williams

Department of Pathology, Preclinical Safety Sciences, GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdom

Malcolm J. York

Clinical Pathology, Cellular and Biochemical Toxicology, Safety Assessment, GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdom

The diagnostic utility of alpha-glutathione S-transferase ({alpha}GST) in the assessment of acute hepatotoxicity was compared with a range of markers including alanine aminotransferas e (ALT) and aspartate aminotransferas e (AST). Rats were given a single oral dose of either {alpha}-naphthylisothiocynate (ANIT), bromobenzen e (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 {alpha}GST, in plasma collected at time points ranging from 3 h to 7 days after dosing. {alpha}GST 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 {alpha}GST were greater than those seen with ALT and AST, yet lower than those seen with glutamate dehydrogenas e (BrB and ANIT), sorbitol dehydrogenas e (TAM), or total bilirubin and bile acids (ANIT). Elevations in {alpha} GST were also detected no earlier than any other marker. {alpha}GST 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.

Key Words: Bromobenzene (BrB) • {alpha}-glutathione S-transferase ({alpha}GST) • hepatic markers • liver enzymes • {alpha}-naphthylisothiocynate (ANIT) • thioacetamide (TAM).

Toxicologic Pathology, Vol. 30, No. 3, 365-372 (2002)
DOI: 10.1080/01926230252929945
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