A Performance Evaluation of Three Drug-Induced Liver Injury Biomarkers in the Rat: Alpha-Glutathione S-Transferase, Arginase 1, and 4-Hydroxyphenyl-Pyruvate Dioxygenase

Bailey, Wendy J.; Holder, Dan; Patel, Hima; Devlin, Pam; Gonzalez, Raymond J.; Hamilton, Valerie; Muniappa, Nagaraja; Hamlin, D. M.; Thomas, Craig E.; Sistare, Frank D.; Glaab, Warren E.

doi:10.1093/toxsci/kfs243

Cited by 44 publications

(23 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gerets et al 51 identified a battery of six cytotoxicity assays to screen pharmaceutical compounds in HepG2 cells using eight drugs. Recently, Bailey et al 52 evaluated 34 acute rat toxicity studies and proposed three novel candidate genes ( GSTA , ARG1 and HPD ) in addition to the established ALT as drug-induced liver injury biomarkers in rats. Complementary to these studies, we present here with the network of EGR1 , ATF3 , GDF15 and FGF21 a signature set detectable as early as 2 h after compound administration.…”

Section: Discussionmentioning

confidence: 99%

Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity

et al. 2013

View full text Add to dashboard Cite

Gene signatures of drug-induced toxicity are of broad interest, but they are often identified from small-scale, single-time point experiments, and are therefore of limited applicability. To address this issue, we performed multivariate analysis of gene expression, cell-based assays, and histopathological data in the TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system) database. Data mining highlights four genes—EGR1, ATF3, GDF15 and FGF21—that are induced 2 h after drug administration in human and rat primary hepatocytes poised to eventually undergo cytotoxicity-induced cell death. Modelling and simulation reveals that these early stress-response genes form a functional network with evolutionarily conserved structure and intrinsic dynamics. This is underlined by the fact that early induction of this network in vivo predicts drug-induced liver and kidney pathology with high accuracy. Our findings demonstrate the value of early gene-expression signatures in predicting and understanding compound-induced toxicity. The identified network can empower first-line tests that reduce animal use and costs of safety evaluation.

show abstract

Section: Discussionmentioning

confidence: 99%

Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The increase in plasma and hepatic levels of 15-F 2t -isoprostane in rats administered VPA was accompanied by an increase in the levels of VPA-G (Tong et al, 2005b). In another in vivo study in rats, hepatic and urinary concentrations of VPA-G did not correlate with serum levels of a-glutathione-S-transferase (Lee et al, 2009), which is a marker of hepatotoxicity (Bailey et al, 2012).…”

Section: Introductionmentioning

confidence: 89%

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

2014

View full text Add to dashboard Cite

Acyl glucuronides are reactive electrophilic metabolites implicated in the toxicity of carboxylic acid drugs. Valproyl 1-O-b-acyl glucuronide (VPA-G), which is a major metabolite of valproic acid (VPA), has been linked to the development of oxidative stress in VPA-treated rats. However, relatively little is known about the toxicity of in situ generated VPA-G and its contribution to VPA hepatotoxicity. Therefore, we investigated the effects of modulating the in situ formation of VPA-G on lactate dehydrogenase (LDH) release (a marker of necrosis), BODIPY 558/568 C 12 accumulation (a marker of steatosis), and cellular glutathione (GSH) content in VPA-treated sandwich-cultured rat hepatocytes. VPA increased LDH release and BODIPY 558/568 C 12 accumulation, whereas it had little or no effect on total GSH content. Among the various uridine 59-diphospho-glucuronosyltransferase inducers evaluated, b-naphthoflavone produced the greatest increase in VPA-G formation. This was accompanied by an attenuation of the increase in BODIPY 558/568 C 12 accumulation, but did not affect the change in LDH release or total GSH content in VPA-treated hepatocytes. Inhibition of in situ formation of VPA-G by borneol was not accompanied by substantive changes in the effects of VPA on any of the toxicity markers. In a comparative study, in situ generated diclofenac glucuronide was not toxic to rat hepatocytes, as assessed using the same chemical modulators, thereby demonstrating the utility of the sandwich-cultured rat hepatocyte model. Overall, in situ generated VPA-G was not toxic to sandwich-cultured rat hepatocytes, suggesting that VPA glucuronidation per se is not expected to be a contributing mechanism for VPA hepatotoxicity.

show abstract

“…Arginase I in blood is one of several recently proposed liver injury biomarkers to be quantified by the Predictive Safety Testing Consortium (PSTC) and the European Medicines Agency. After evaluating three potential biomarkers (alphaglutathione-S-transferase, arginase I, and 4-hydroxyphenylpyruvate dioxygenase) in 34 acute liver toxicity rats, Bailey et al reported that arginase I was the most sensitive biomarker to predict biliary injury, and more specific compared with ALT and the other two potential biomarkers [40]. Blood arginine levels can also be affected by nitric oxide synthases (NOSs), which convert arginine to citrulline and nitric oxide (NO; an important signaling molecule to control blood pressure, insulin secretion and nervous system development, etc.).…”

Section: Discussionmentioning

confidence: 99%

Systems Biology Investigation to Discover Metabolic Biomarkers of Acetaminophen-Induced Hepatic Injury Using Integrated Transcriptomics and Metabolomics

2013

J Mol Biomark Diagn

View full text Add to dashboard Cite

A Performance Evaluation of Three Drug-Induced Liver Injury Biomarkers in the Rat: Alpha-Glutathione S-Transferase, Arginase 1, and 4-Hydroxyphenyl-Pyruvate Dioxygenase

Cited by 44 publications

References 33 publications

Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity

Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

Systems Biology Investigation to Discover Metabolic Biomarkers of Acetaminophen-Induced Hepatic Injury Using Integrated Transcriptomics and Metabolomics

Contact Info

Product

Resources

About