title: A performance evaluation of three drug-induced liver injury biomarkers in the rat: alpha-glutathione S-transferase, arginase 1, and 4-hydroxyphenyl-pyruvate dioxygenase.
abstract: Alanine aminotransferase (ALT) activity is the most frequently relied upon reference standard for monitoring liver injury in humans and nonclinical species. However, limitations of ALT include a lack of specificity for diagnosing liver injury (e.g., present in muscle and the gastrointestinal tract), its inability to monitor certain types of hepatic injury (e.g., biliary injury), and ambiguity with respect to interpretation of modest or transient elevations (< 3× upper limit of normal). As an initial step to both understand and qualify additional biomarkers of hepatotoxicity that may add value to ALT, three novel candidates have been evaluated in 34 acute toxicity rat studies: (1) alpha-glutathione S-transferase (GSTA), (2) arginase 1 (ARG1), and (3) 4-hydroxyphenylpyruvate dioxygenase (HPD). The performance of each biomarker was assessed for its diagnostic ability to accurately detect hepatocellular injury (i.e., microscopic histopathology), singularly or in combination with ALT. All three biomarkers, either alone or in combination with ALT, improved specificity when compared with ALT alone. Hepatocellular necrosis and/or degeneration were detected by all three biomarkers in the majority of animals. ARG1 and HPD were also sensitive in detecting single-cell necrosis in the absence of more extensive hepatocellular necrosis/degeneration. ARG1 showed the best sensitivity for detecting biliary injury with or without ALT. All the biomarkers were able to detect biliary injury with single-cell necrosis. Taken together, these novel liver toxicity biomarkers, GSTA, ARG1, and HPD, add value (both enhanced specificity and sensitivity) to the measurement of ALT alone for monitoring drug-induced liver injury in rat.
authors.affiliation: Safety Assessment and Laboratory Animal Resources, Merck and Co., Inc., WP45-323, 770 Sumneytown Pike, West Point, PA 19486, USA. wendy_bailey@merck.com
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Bailey
authors.forename: Dan
authors.initials: D
authors.lastname: Holder
authors.forename: Hima
authors.initials: H
authors.lastname: Patel
authors.forename: Pam
authors.initials: P
authors.lastname: Devlin
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Gonzalez
authors.forename: Valerie
authors.initials: V
authors.lastname: Hamilton
authors.forename: Nagaraja
authors.initials: N
authors.lastname: Muniappa
authors.forename: Diane M
authors.initials: DM
authors.lastname: Hamlin
authors.forename: Craig E
authors.initials: CE
authors.lastname: Thomas
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sistare
authors.forename: Warren E
authors.initials: WE
authors.lastname: Glaab
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000378:metabolism*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D016014:Linear Models; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016015:Logistic Models; D008297:Male; D011237:Predictive Value of Tests; D012372:ROC Curve; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D015415:Biomarkers; D007527:Isoenzymes; D015111:4-Hydroxyphenylpyruvate Dioxygenase; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D000410:Alanine Transaminase; D001119:Arginase; C542908:arginase I, rat