Identification of toxicologically predictive gene sets using cDNA microarrays

Thomas, Russell S.; Rank, David R.; Penn, Sharron G.; Zastrow, Gina M.; Hayes, Kevin; Pande, Kalyan; Glover, Edward; Silander, Tomi; Craven, Mark; Reddy, Janardan K.; Jovanovich, Stevan; Bradfield, Christopher A.

doi:10.1124/mol.60.6.1189

Cited by 228 publications

(97 citation statements)

References 14 publications

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“…The microarrays used for the analysis were produced by the Bradfield lab; for more details on the construction of these microarrays see Thomas et al, 2001. A threshold 2-fold change in gene expression was used as a cutoff.…”

Section: Mrna Microarray Studymentioning

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: Mrna Microarray Studymentioning

confidence: 99%

“…A threshold 2-fold change in gene expression was used as a cutoff. For further details of the procedures and statistical analysis, see Thomas et al (2001).…”

Section: Mrna Microarray Studymentioning

confidence: 99%

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

Uetrecht

2008

Journal of Immunotoxicology

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“…Some of those described to date include the presence of a parent compound or metabolite (Hecht 2002); proliferation and differentiation indices (Iatropoulos and Williams 1996); apoptotic end points (Samaha et al 1997); formation of DNA adducts or damage (Poirier and Weston 1996); chromosomal abnormalities (Lucas 1997); micronuclei formation (Schoket et al 1999); expression of specific genes (Riggins 2001); changes in gene expression profile (single or multiple genes) (Thomas et al 2001); and measurement of enzyme activity (Chen et al 1999), to name but a few. In some cases different biomarkers can be used to measure the same indicator.…”

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confidence: 99%

Biomarkers for assessing reproductive development and health: Part 1--Pubertal development.

Rockett

Lynch

Buck

2004

Environ Health Perspect

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The proposed National Children's Study has helped raise awareness of the issues related to children's health and the importance of monitoring the growth and development of children from preconception through adulthood. Many genetic predispositions can adversely impact the normal development process, and various environmental exposures have been linked to adverse reproductive health in rodent models and a small number of accidental human exposures. To monitor reproductive health and identify adverse effects at the earliest possible juncture, investigators must develop a network of biomarkers covering all stages and aspects of reproductive development and function. Biomarkers are biological indicators that can be measured repeatedly and are informative on one or more aspects of biological development or function. They can range from the anatomical level down to the molecular level and may provide information on the nature of an exposure, the effect of an exposure, or the susceptibility of individuals or populations to the toxic effects of an exposure. In theory, biomarkers can be used to monitor a wide variety of conditions and responses ranging from abnormal development to early indicators of late-onset disease. The main stumbling block with this theory has been finding appropriate biomarkers for particular conditions and exposures. Such biomarkers must be easily accessible, robust, and sensitive. Ideally, they will be expressed across a large section of the population, and can be monitored quickly, easily, conveniently, and with minimal cost. In this review, we discuss some of the current and emerging biomarkers of human pubertal development.

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“…Microarrays are used to characterize changes in gene expression due to a toxicant of interest, identify genes up-or down-regulated, map regulatory pathways modulated by the toxicant, and, in the case of CWAs, identify potential therapeutic targets in these pathways (Thomas et al, 2001;Hamadeh et al, 2002). In addition, microarrays can be used to examine the role of microRNA (miRNA) in chemical toxicity.…”

Section: Genomicsmentioning

confidence: 99%

Genomics and proteomics in chemical warfare agent research: Recent studies and future applications

Everley¹,

Dillman²

2010

Toxicology Letters

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a b s t r a c tMedical research on the effects of chemical warfare agents (CWAs) has been ongoing for nearly 100 years, yet these agents continue to pose a serious threat to deployed military forces and civilian populations. CWAs are extremely toxic, relatively inexpensive, and easy to produce, making them a legitimate weapon of choice for terrorist organizations. While the mechanisms of action for many CWAs have been known for years, questions about their molecular effects following acute and chronic exposure remain largely unanswered. Global approaches that can pinpoint which cellular pathways are altered in response to CWAs and characterize long-term toxicity have not been widely used. Fortunately, innovations in genomics and proteomics technologies now allow for thousands of genes and proteins to be identified and subsequently quantified in a single experiment. Advanced bioinformatics software can also help decipher large-scale changes observed, leading to mapping of signaling pathways, functional characterization, and identification of potential therapeutic targets. Here we present an overview of how genomics and proteomics technologies have been applied to CWA research and also provide a series of questions focused on how these techniques could further our understanding of CWA toxicity.

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Identification of toxicologically predictive gene sets using cDNA microarrays

Cited by 228 publications

References 14 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

Biomarkers for assessing reproductive development and health: Part 1--Pubertal development.

Genomics and proteomics in chemical warfare agent research: Recent studies and future applications

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