A gene expression signature for oxidant stress/reactive metabolites in rat liver

McMillian, Michael; Nie, Alex; Parker, J. Brandon; Leone, Angelique; Bryant, Stewart; Kemmerer, Matthias; Herlich, Judy; Liu, Yanhong; Yieh, Lynn; Bittner, Anton; Liu, Xuejun; Wan, Jackson; Johnson, Mark D.

doi:10.1016/j.bcp.2004.08.003

Cited by 82 publications

(55 citation statements)

References 40 publications

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“…A recent study applied toxicogenomics profiling to differentiate chemical reagents known to cause hepatotoxicity and oxidative stress into three subcategories: macrophage activators (MA), peroxisome proliferators (PP), and oxidative stressors/reactive metabolites (OS/RM) (McMillian et al, 2004a(McMillian et al, , 2004b(McMillian et al, , 2005. A supervised training/testing approach was used to differentiate MA, PP, and OS/RM gene transcriptional signature patterns in rat liver.…”

Section: Discussionmentioning

confidence: 99%

“…Gene expression responses were selected that best separated the training set samples from all other treated and control samples. Transcription factors that distinguished the OS/RM class, such as Gst mu1 and heat shock proteins, are related to the Keap1-Nrf2-ARE signaling pathway (McMillian et al, 2004a(McMillian et al, , 2004b(McMillian et al, , 2005, which is believed to be a response to oxidative or electrophilic stress and promote cell survival (Talalay et al, 2003;Dinkova-Kostova et al, 2005;Shen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In our study, 20 out of 30 of most up-regulated genes from both CBZ-and PHN-treated mice overlap with the list of genes used as the gene set used to distinguish oxidative stressors that belong to the OS/RM class (McMillian et al, 2004a(McMillian et al, 2004b and also overlap with the list of genes involved in the Keap1-Nrf2-ARE signaling pathway (Kwak et al, 2003). This suggests that CBZ and PHN or their metabolites are responsible for an oxidative stress response that disrupts the Keap1-Nrf2 complex and serves as the common mechanism shared by both drugs.…”

Section: Discussionmentioning

confidence: 99%

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Changes in Gene Expression Induced by Carbamazepine and Phenytoin: Testing the Danger Hypothesis

Uetrecht

2008

Journal of Immunotoxicology

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The aromatic anticonvulsants carbamazepine (CBZ) and phenytoin (PHN) are associated with a relatively high incidence of idiosyncratic drug reactions (IDRs). If biomarkers could be found that would predict the risk that a drug candidate would cause IDRs it would significantly decrease the risks associated with drug development. The IDRs associated with CBZ and PHN appear to be immune-mediated. The Danger Hypothesis posits that for something to induce an immune response, it must cause some type of cell damage that ultimately causes up-regulation of co-stimulatory molecules on antigen-presenting cells; without this, the response will be immune tolerance. If the Danger Hypothesis is correct, the ability of a drug or its reactive metabolite to induce cell damage or stress may be related to its risk of causing IDRs. In a parallel study reported elsewhere, we found that major metabolites of these two drugs: 3-OH-CBZ and 4-OH-PHN can be oxidized by peroxidases to phenoxyl free radicals, which could cause oxidative stress by redox cycling. In this study using mRNA microarrays, we found that CBZ and PHN treatment induced changes in mRNA expression in mice. Many of the changes were in genes related to Keap1-Nrf2-ARE signaling pathways and enzymes involved in responding Abbreviations: AP-1, activator protein 1; PPARα, peroxisome proliferator-activated receptor α; ARE, antioxidant response element; CBZ, carbamazepine; Cp, crossing point; GST, glutathione S-transferase; Gapdh, glyceraldehydes-3-phosphate dehydrogenase; HSP, heat shock protein; IDR, idiosyncratic drug reaction; Keap1, Kelch-like ECH-associated protein 1; MA, Macrophage activators; NF-κB, nuclear factor κB; Nrf2, nuclear factor-erythroid 2-related factor 2; 3-OH-CBZ, 3-hydroxycarbamazepine; 4-OH-PHN, 4-hydroxyphenytoin; OS/RM, oxidative stressors/reactive metabolites; PCR, polymerase chain reaction; PHN, phenytoin, 5,5-diphenylhydantoin; PP, peroxisome proliferators; ROS, reactive oxygen species; Stat-3, signal transducers and activators of transcription-3; UDPG, uridine diphosphoglucose.Current address for Wei Lu: Biotransformation, Drug Safety and Metabolism, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426.Address correspondence to Jack Uetrecht, MD, PhD, Leslie Dan Faculty of Pharmacy, Room 1010, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2; e-mail jack.uetrecht@utoronto.ca to oxidant stressors and reactive metabolites such as glutathione transferase and heat shock proteins. The similar patterns of genes induced by these two drugs are consistent with the clinical observation that those two drugs exhibit cross-sensitivity. These findings are consistent with the induction of cell stress by CBZ and PHN, most likely due to reactive metabolites. Such changes may represent a danger signal and represent a biomarker of the potential that a drug will cause IDRs; however, different drugs likely cause cell stress by different mechanisms and, therefore, the biomarkers for other drugs would likely be different.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Changes in Gene Expression Induced by Carbamazepine and Phenytoin: Testing the Danger Hypothesis

Uetrecht

2008

Journal of Immunotoxicology

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“…The expression level of NQO1 increased significantly in Groups 2 and 3. NQO1 is a flavoprotein that catalyzes the metabolic detoxification of quinones, which are also formed in the biotransformation of BB (Jaiswal, 2000;Long et al, 2000;McMillian et al, 2004). It was suggested, therefore, that EH-and NQO1-mediated hydrolysis in addition to glutathione conjugation was enhanced in the liver along with the resistance.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Resistance to Bromobenzene-Induced Hepatotoxicity by Microarray

et al. 2007

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-In our previous study, we demonstrated that the initial hepatic injury caused by bromobenzene (BB) was no longer detected in rats despite subsequent dosing, indicating that the liver acquired resistance to BB-induced hepatotoxicity. In this experiment, microarray analysis was conducted to characterize this resistance. The liver samples for the analysis utilized were obtained from previous experiments where F344 rats were treated intraperitoneally with BB (150 mg/kg). At 24 hr post-dose, hepatic injury was confirmed by monitoring the AST values and then the rats were maintained at the same dosing regimen for an additional 8 days. The gene expression profiles of the BB-treated rat livers were compared with a vehicle-treated group by Affymetrix RG_U34A arrays. As results, a decreased expression level of CYP3A9 and an increased expression level of GST Yc2 and glutathione peroxidase (GPX) were detected. These changes indicated suppression of the phase I reaction and induction of the phase II reaction (glutathione conjugation). Increased expression levels of epoxide hydrolase (EH) and NAD(P)H:quinone oxidoreductase (NQO1) also suggested the involvement of EH-and NQO1-mediated hydrolysis other than glutathione conjugation with resistance in the phase II reaction. Moreover, an increased expression level of abcc3 (multidrug resistance protein 3; Mrp3) was significantly noted. Based on the present findings, it was suggested that Mrp3 in the phase III reaction (drug elimination) contributed to the resistance to BB hepatotoxicity in addition to the suppression of the phase I reaction (metabolic activation) and the induction of the phase II reaction (detoxification). Among them, the factors which contributed most were considered to be the increased GST Yc2 and Mrp3, based on the degree of the gene expression changes.

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“…Hepatotoxicants were categorize over 100 paradigm compounds as to their oxidative stress potential in rat liver [80]. Effect of the ecotoxicity of silver nanoparticles (AgNPs) in Caenorhabditis elegans using survival, growth, and reproduction, as the ecotoxicological endpoints, as well as stress response gene expression studied.…”

Section: Drug Toxicogenomicsmentioning

confidence: 99%

Toxicogenomics and cancer pathogenesis

Gupta¹,

AK²,

Boraste³

et al. 2009

Int J Genet

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Abstract-Toxicogenomics is emerging field give idea of the application of large-scale differential gene expression data to toxicology, starting to influence drug discovery and development in the pharmaceutical industry. Its future potential in cancer pathogenesis, study of poisons and poisoning and has an ancient and venerable history. Toxicogenomics is the merging of toxicology with technologies that have been developed, together with bioinformatics, to identify and quantify global gene expression changes for gene therapy. Immunotoxic processes and the development of in vitro screening assays is therefore expected to be of value for mechanistic insight into immunotoxicity and hazard identification of existing and novel compounds. Successful application of toxicogenomic approaches, such as DNA microarrays, inextricably relies on appropriate data management, the ability to extract knowledge from massive amounts of data and the availability of functional information for data interpretation. Toxicogenomics is considered a valuable tool for reducing pharmaceutical candidate attrition by facilitating earlier identification, prediction and understanding of toxicities. Pharmaco-epidemiological (toxicogenomics) data is now available for both antiepileptic drugs, evidence for human carcinogenicity. Therapeutic researches converge triad of rejuvenation, regeneration or replacement strategies that rely on self-healing processes, stem cell regeneration organ transplantation. Metastases studies usually display more genetic changes than the primary tumour. Helix-loop-helix application in translational and functional toxicogenomics transcription factors has been implicated in diverse cellular processes such as proliferation, apoptosis, differentiation, and migration.

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A gene expression signature for oxidant stress/reactive metabolites in rat liver

Cited by 82 publications

References 40 publications

Changes in Gene Expression Induced by Carbamazepine and Phenytoin: Testing the Danger Hypothesis

Changes in Gene Expression Induced by Carbamazepine and Phenytoin: Testing the Danger Hypothesis

Characterization of Resistance to Bromobenzene-Induced Hepatotoxicity by Microarray

Toxicogenomics and cancer pathogenesis

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