title: Assessment of emerging biomarkers of liver injury in human subjects.
abstract: Hepatotoxicity remains a major challenge in drug development. Although alanine aminotransferase (ALT) remains the gold standard biomarker of liver injury, alternative biomarker strategies to better predict the potential for severe drug-induced liver injury (DILI) are essential. In this study, we evaluated the utility of glutamate dehydrogenase (GLDH), purine nucleoside phosphorylase (PNP), malate dehydrogenase (MDH), and paraxonase 1 (PON1) as indicators of liver injury in cohorts of human subjects, including healthy subjects across age and gender, subjects with a variety of liver impairments, and several cases of acetaminophen poisoning. In the healthy subjects, levels of GLDH and MDH were not affected by age or gender. Reference ranges for GLDH and MDH in healthy subjects were 1-10 and 79-176U/L, respectively. In contrast, the levels of PON1 and PNP were not consistent across cohorts of healthy subjects. Furthermore, GLDH and MDH had a strong correlation with elevated ALT levels and possessed a high predictive power for liver injury, as determined by ROC analysis. In contrast, PON1 and PNP did not detect liver injury in our study. Finally, evaluation of patients with acetaminophen-induced liver injury provided evidence that both GLDH and MDH might have utility as biomarkers of DILI in humans. This study is the first to evaluate GLDH, MDH, PON1, and PNP in a large number of human subjects and, and it provides an impetus for prospective clinical studies to fully evaluate the diagnostic value of GLDH and MDH for detection of liver injury.
authors: Drug Safety R&D, Pfizer Inc., Groton, Connecticut 06340, USA.
authors: Shelli
authors: S
authors: Schomaker
authors: Roscoe
authors: R
authors: Warner
authors: Jeff
authors: J
authors: Bock
authors: Kent
authors: K
authors: Johnson
authors: David
authors: D
authors: Potter
authors: Joyce
authors: J
authors: Van Winkle
authors: Jiri
authors: J
authors: Aubrecht
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000410:Alanine Transaminase / Q000097:blood; D043303:Aryldialkylphosphatase / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood*; D005260:Female; D005969:Glutamate Dehydrogenase / Q000097:blood; D006801:Humans; D008291:Malate Dehydrogenase / Q000097:blood; D008297:Male; D011683:Purine-Nucleoside Phosphorylase / Q000097:blood
chemical_list: D015415:Biomarkers; D000082:Acetaminophen; D008291:Malate Dehydrogenase; D005969:Glutamate Dehydrogenase; D011683:Purine-Nucleoside Phosphorylase; D000410:Alanine Transaminase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human