Diagnostic and predictive performance and standardized threshold of traditional biomarkers for drug‐induced liver injury in rats

Abstract

Traditional biomarkers such as alanine and aspartate aminotransferase (ALT, AST) and total bilirubin (TBIL) have been widely used for detecting drug-induced liver injury (DILI). Although the Food and Drug Administration (FDA) proposed standardized thresholds for human as Hy's law, those for animals have not been determined, and predictability of these biomarkers for future onset of hepatic lesions remains unclear. In this study, we investigated these diagnostic and predictive performance of 10 traditional biomarkers for liver injury by receiver-operating characteristic (ROC) curve, using a free-access database where 142 hepatotoxic or non-hepatotoxic compounds were administrated to male rats (n=5253). Standardization of each biomarker value was achieved by calculating the ratio to control mean value, and the thresholds were determined under the condition of permitting 5% false positive. Of these 10 biomarkers, AST showed the best diagnostic performance. Furthermore, ALT and TBIL also showed high performance under the situation of hepatocellular necrosis and bile duct injury, respectively. Additionally, the availability of the diagnostic thresholds in difference testing facility was confirmed by the application of these thresholds to in-house prepared dataset. Meanwhile, incorrect diagnosis by the thresholds was also observed. Regarding prediction, all 10 biomarkers showed insufficient performance for future onset of hepatic lesions. In conclusion, the standardized diagnostic thresholds enable consistent evaluation of traditional biomarkers among different facilities, whereas it was suggested that novel biomarker is required for more accurate diagnosis and prediction of DILI.

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“…This increased effect was in accordance with other studies. For instance, studies have shown that ALT is more specific for liver than AST as the later was also seen in muscle damage 14,15 .…”

“…For example, increased levels of liver enzymes, alanine and aspartate aminotransferases (ALT and AST, respectively), widely used serum biomarkers for liver toxicity 13 . Studies have shown that ALT is more specific for liver than AST as the later was also seen in muscle damage 14,15 . Remedies of herbal extracts have been used to reduce the adverse effects and protect against drug liver toxicity, and they have been used at preclinical and clinical levels 16 .…”

A New Structure-Activity Relationship (SAR) Model for Predicting Drug-Induced Liver Injury, Based on Statistical and Expert-Based Structural Alerts

“…Alanine and aspartate aminotransferase (ALT and AST), alkaline phosphatase (ALP), total bilirubin (TBIL) and γ-glutamyltransferase (GGT) are considered the reference biomarkers and are widely employed for the detection of DILI, providing supporting information in pre-clinical and clinical toxicity studies for drug development (US FDA, 2009; Tonomura et al, 2015). However, they are not always specific and sensitive in recognizing liver diseases provoked by DILI or other causes such as viruses (Przybylak and Cronin, 2012).…”

Reconciled Rat and Human Metabolic Networks for Comparative Toxicogenomics Analyses

“…Traditional biomarkers used in preclinical drug development include proteins such as albumin, aspartate aminotransferase, and alkaline phosphatase and metabolites such as bilirubin, creatinine, and triglycerides 5 . Although these biomarkers can effectively diagnose DILI, traditional biomarkers are limited in scope to accurately predict future onset of DILI 6 . High-throughput metabolomics methods have the potential to significantly improve both diagnostic and predictive biomarkers of DILI by expanding the potential pool of biomarkers from a few dozen to thousands of metabolites [7][8][9] .…”

“…High-throughput metabolomics methods have the potential to significantly improve both diagnostic and predictive biomarkers of DILI by expanding the potential pool of biomarkers from a few dozen to thousands of metabolites [7][8][9] . In contrast to biomarkers like aspartate aminotransferase, which are released into the blood after hepatocellular membrane disintegration 6 , we anticipate that metabolite biomarkers will require less catastrophic perturbations to be detected and will be more sensitive to the direct mechanisms of hepatocyte injury 6 . Preclinical efforts to identify biomarkers associated with toxicity typically use statistical methods that correlate changes in metabolite concentrations with toxicant exposure [7][8][9][10][11][12][13] .…”