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7 Application to the Study of Mechanisms of Action
Pages 107-120

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From page 107...
... Current risk assessment processes use mechanistic understanding to detect or identify hazards and to make decisions about dose-response relationships. However, despite general acceptance of the concept that mechanistic information is valuable for understanding the basis of the toxic response, data from mechanism-based investigations are not incorporated into risk assessment paradigms as often because either understanding of the mechanism of toxicity is incomplete or competing hypotheses exist.
From page 108...
... As such, these changes under defined conditions of cellular location, time, and biologic context can provide meaningful information about biologic responses to toxic insult. Thus, toxicogenomic studies offer a new dimension in environmental exposure assessment, drug and chemical screening, and understanding of human and animal variability in response to drugs and chemicals.
From page 109...
... Combining transcriptional analysis with parallel or correlational analyses of both protein and metabolite profiles makes it possible to examine the multidimensionality of the toxic response. The study of mechanisms is complicated by the fact that toxicity often involves complex interactions of chemicals with genes, proteins, and cellular metabolic intermediates.
From page 110...
... Contextual Approach to Study Mechanisms of Action The contextual approach (Box 7-1) to studying mechanisms of action places newly discovered information within the context of the larger body of biologic and toxicologic knowledge, comparing newly generated toxicogenomic data from a test chemical with data from compounds whose mechanism of action is better understood.
From page 111...
... In this scenario, genes identified by using a contextual design are disrupted pharmacologically, genetically, or molecularly and the genome-wide response is reevaluated to gain more detailed information and additional mechanistic insight. For example, pharmacologic agents or molecular interventions such as posttranscriptional gene silencing, also known as RNA interference, are used to selectively target genes of interest and test specific hypotheses that involve studying gene-gene associations that emerged from transcriptional profiling experiments (Hannon and Rossi 2004)
From page 112...
... (2001) identified a set of genes useful for predicting toxicity using transcriptome profiles for 24 hepatotoxic compounds representing five toxicologic categories (peroxisome proliferators, AhR agonists, noncoplanar polychlorinated biphenyls, inflammatory agents, and hypoxiainducing agents)
From page 113...
... Network Building Approach to Study Mechanisms of Action The third experimental approach uses patterns of transcriptional coregulation and targeted genetic manipulations to identify biologic interaction networks involved in toxicity. This type of experiment uses relational biologic information to place the toxicologic response within the complex framework that mediates the biologic response.
From page 114...
... (2004) , who investigated signal transduction pathways evoked by AhR activation, reported another example of network building.
From page 115...
... Although many of the changes observed may encode mechanistic information about chemically induced injury, distinguishing proteomic changes that represent causes versus effects requires more sophisticated experimental approaches. As described in Chapter 2, one such study recently described the application of quantitative shotgun proteomics using isotope-coded affinity tag labels to compare proteomes of mice that are susceptible or resistant to the hepatotoxic analgesic acetaminophen both before and after drug treatment (Welch et al.
From page 116...
... Proteomic approaches can go beyond traditional toxicologic approaches in identifying molecular targets of injury and delineating mechanisms of toxicity. Covalent binding has long been known to contribute to toxicity in many cases, but mechanistic insights have been limited by a lack of knowledge about protein targets of reactive intermediates (Cohen et al.
From page 117...
... Serial measurements enable metabolite status to be correlated with timedependent changes in other parameters, and this allows inferences about specific metabolic pathway changes during the course of toxicity and recovery. Most studies to date have applied NMR- and MS-based metabonomic analyses to animal models of tissue-specific toxicity.
From page 118...
... CONCLUSIONS Toxicogenomic studies are improving our knowledge of the underlying biology and the regulatory networks that integrate the signaling cascades involved in toxicity. Thus, toxicogenomic data may advance the introduction of mechanistic insight into risk assessment and fulfill the promise of more accurate and expedited elucidation of class-related biologic effects or predictive toxicity.
From page 119...
... The application of toxicogenomic approaches to the study of toxicity has advanced our understanding of the biology that underlies the deleterious actions of chemical and pharmaceutical agents on living systems, the regulatory networks that integrate the signaling cascades involved in toxicity, and the pathogenesis of environmental or drug-induced disease. Indeed, mechanistic toxicology investigations have proven useful in risk assessment, drug development, environmental exposure assessment, and understanding of human and animal variability in response to drugs and chemicals.
From page 120...
... 6. Implement educational programs to help the toxicology and risk assessment communities incorporate toxicogenomic approaches and data-rich mechanistic assessments into their professional practice.


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