Applications of microarrays with toxicologically relevant genes (tox genes) for the evaluation of chemical toxicants in Sprague Dawley rats in vivo and human hepatocytes in vitro

Kier, Larry D.; Neft, Robin E.; Tang, Lei; Suizu, Robert; Cook, Tari; Onsurez, Kathy; Tiegler, Karen; Sakai, Yumiko; Ortiz, Michael; Nolan, Tim; Sankar, Usha; Li, Albert P.

doi:10.1016/j.mrfmmm.2003.11.015

Cited by 100 publications

(18 citation statements)

References 31 publications

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“…As observed in rat hepatocytes, Kier and coworkers [87] showed that TRO induced more genes than ROSI in human hepatocytes. This observation was based on analysis of gene expression profiles and did not include individual characterization of deregulated genes.…”

Section: In Vitro Human Liver Cell Studiesmentioning

confidence: 92%

Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver

et al. 2010

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Thiazolidinediones are a class of Peroxisome Proliferator Activated Receptor γ (PPARγ) agonists that reduce insulin resistance in type 2 diabetic patients. Although no detectable hepatic toxicity has been evidenced in animal studies during preclinical trials, these molecules have nevertheless induced hepatic adverse effects in some treated patients. The mechanism(s) of hepatotoxicity remains equivocal. Several studies have been conducted using PCR analysis and microarray technology to identify possible target genes and here we review the data obtained from various in vivo and in vitro experimental models. Although PPARγ is expressed at a much lower level in liver than in adipose tissue, PPARγ agonists exert various PPARγ-dependent effects in liver in addition to PPARγ-independent effects. Differences in effects are dependent on the choice of agonist and experimental conditions in rodent animal studies and in rodent and human liver cell cultures. These effects are much more pronounced in obese and diabetic liver. Moreover, our own recent studies have shown major interindividual variability in the response of primary human hepatocyte populations to troglitazone treatment, supporting the occurrence of hepatotoxicity in only some individuals.

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Section: In Vitro Human Liver Cell Studiesmentioning

confidence: 92%

Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver

et al. 2010

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“…Large screening studies in hepatocytes examining changes in gene expression have shown that idiosyncratic toxicants (troglitazone, trovafloxacin) alter gene expression patterns much more than their non-hepatotoxic counterparts, possibly due to the stress and injury they inflict [58,59]. Many of these changes in hepatocytes are likely involved in adaptation to the drug.…”

Section: Signaling Pathways Involved In Idiosyncratic Hepatotoxicitymentioning

confidence: 99%

Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria

Han

Dara

Win

et al. 2013

Trends in Pharmacological Sciences

159

140

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Drugs that cause liver injury often “stress” mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Due to adaptation, drugs alone rarely cause liver injury, with acetaminophen being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause “stressed” hepatocytes to become injured; leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as JNK become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI.

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“…Proper study design can help reduce the complexity of biological interpretation of the results. Many toxicogenomics studies incorporate multiple doses and multiple time points into the study design (Amin et al 2004; Bulera et al 2001; Hamadeh et al 2004, 2002; Heijne et al 2003; Heinloth et al 2004; Kier et al 2004; Lühe et al 2003; Ruepp et al 2002), but based on results from this study, we also recommend obtaining gene expression data from a nontarget tissue, in addition to using multiple dose levels and time points, for the purpose of clarifying the biological relevance of the observed expression changes in the target tissue for toxicity.…”

Section: Discussionmentioning

confidence: 99%

Identification of Genes Implicated in Methapyrilene-Induced Hepatotoxicity by Comparing Differential Gene Expression in Target and Nontarget Tissue

Auman

Chou

Gerrish

et al. 2007

Environ Health Perspect

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BackgroundToxicogenomics experiments often reveal thousands of transcript alterations that are related to multiple processes, making it difficult to identify key gene changes that are related to the toxicity of interest.ObjectivesThe objective of this study was to compare gene expression changes in a nontarget tissue to the target tissue for toxicity to help identify toxicity-related genes.MethodsMale rats were given the hepatotoxicant methapyrilene at two dose levels, with livers and kidneys removed 24 hr after one, three, and seven doses for gene expression analysis. To identify gene changes likely to be related to toxicity, we analyzed genes on the basis of their temporal pattern of change using a program developed at the National Institute of Environmental Health Sciences, termed “EPIG” (extracting gene expression patterns and identifying co-expressed genes).ResultsHigh-dose methapyrilene elicited hepatic damage that increased in severity with the number of doses, whereas no treatment-related lesions were observed in the kidney. High-dose methapyrilene elicited thousands of gene changes in the liver at each time point, whereas many fewer gene changes were observed in the kidney. EPIG analysis identified patterns of gene expression correlated to the observed toxicity, including genes associated with endoplasmic reticulum stress and the unfolded protein response.ConclusionsBy factoring in dose level, number of doses, and tissue into the analysis of gene expression elicited by methapyrilene, we were able to identify genes likely to not be implicated in toxicity, thereby allowing us to focus on a subset of genes to identify toxicity-related processes.

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Applications of microarrays with toxicologically relevant genes (tox genes) for the evaluation of chemical toxicants in Sprague Dawley rats in vivo and human hepatocytes in vitro

Cited by 100 publications

References 31 publications

Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver

Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver

Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria

Identification of Genes Implicated in Methapyrilene-Induced Hepatotoxicity by Comparing Differential Gene Expression in Target and Nontarget Tissue

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