Toxicogenomics

Toxicogenomics could potentially help reduce the time it takes for drug companies to perform the required safety evaluations on new compounds and perhaps lessen the likelihood of late stage (and expensive) toxicological surprises. 

Rosenstiel School of Marine and Atmospheric Sciences, University of Miami, Miami, Florida, 33149 

Molecular and Biochemical Toxicology, Fourth Edition, edited by Robert C. Smart and Ernest Hodgson Copyright 2008 John Wiley Sons, Inc. 

Genomics is steeped in a specialized vocabulary. Table 3.1 summarizes much of this vocabulary. 

Enhancer DNA sequence that binds a transcription factor. Enhancers typically are not part of the proximal promoter and often are effective from a long distance, in either orientation, 5 or 3 to a gene. 

EST Expressed sequence tag, a short (100s bp) partial nucleotide sequence from a full-length or nearly full-length cDNA. These sequences are usually from the 5 or 3 ends of directionally cloned inserts as part of high-throughput sequencing projects. The partial cDNA sequence provides annotation by similarity searches and the putative identification of function. 

Examples of immunotoxicogenomic studies that have appeared in the literature (reviewed by Baken et al. [132] and Burns-Naas et al. [133]) show that microarray analysis is able to detect known and novel effects of a wide range of immunomo-dulating agents, but they also indicate several pitfalls. The impact of duration of exposure and dose level on the outcome of microarray analysis was for instance illustrated by a series of experiments on the immunosuppressive model compound bis(tri-n-butyl)tinoxide (TBTO). Induction of thymocyte apoptosis by TBTO appeared to precede inhibition of cell proliferation, since the former was found after short 

The use of both low and high doses in a study on hexachlorobenzene (HCB) by Ezendam et al. [135] revealed the complexity of cells and mediators that participate in the response to this compound. Such approaches may provide valuable insight into gene expression changes in the presence and absence of pathological or cellular effects. 

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Toxicology ( toxicogenomics), to identify potential human and environmental toxicants, and to find correlations between toxic responses to toxicants and changes in the genetic profiles of the objects exposed to such toxicants... 

Burczynski, M. (Ed.) (2003). An Introduction to Toxicogenomics—Describes, with examples, the use of genomic techniques in toxicology. 

Finne, E.F., Cooper, G.A., and Koop, B.F. et al. (2007). Toxicogenomic responses in rainbow trout Oncorhynchus mykiss) hepatocytes exposed to model chemicals and a synthetic mixture. Aquatic Toxicology 81, 293-303. 

Castle AL, Carver MP, Mendrick DL. Toxicogenomics a new revolution in drug safety. Drug Discov Today 2002 7 728-36. 

McMillian M, Nie A, Parker JB, Leone A, Kemmerer M, Bryant S, et al. Drug-induced oxidative stress in rat liver from a toxicogenomics perspective. Toxicol Appl Pharmacol 2005 207 171-8. 

Waters M, Boorman G, Bushel P, Cunningham M, Irwin R, Merrick A, et al. Systems toxicology and the Chemical Effects in Biological Systems (CEBS) knowledge base. EHP Toxicogenomics 2003 111 15-28. 

It is imperative, however, to understand the probabilistic nature of such experiments a promising profile on pharmacogenomic and toxicogenomic screens will enhance the likelihood of having selected an ultimately successful compound, and will achieve this goal quicker than conventional animal experimentation, but will do so only with a certain likelihood of success. The less reductionist approach of the animal experiment will still be needed. It is to be anticipated, however, that such approaches will constitute an important, time- and resource-saving first evaluation or screening step that will help to focus and reduce the number of animal experiments that will ultimately need to be conducted. 

To Err is Human" Institute of Medicine Report, 220 ToxChip, 147 Toxicity issues, 41, 211 Toxicogenomics, 43, 89, 146-147 Toxicogenomics laboratories, 153 Toxicological tests, 88-89 TPMT gene, x... 

Burchiel, S.W. et al., Analysis of genetic and epigenetic mechanisms of toxicity potential roles of toxicogenomics and proteomics in toxicology, Toxicol. Sci., 59, 193, 2001. 

Waring, J. F. et al., Development of a DNA microarray for toxicology based on hepato-toxin-regulated sequences, EHP Toxicogenomics, 111, 53, 2003. 

Ezendam, J. et al., Toxicogenomics of subchronic hexachlorobenzene exposure in Brown Norway rats, Environ. Health. Perspect., 112, 782, 2004. 

Luhe, A. et al., Toxicogenomics in the pharmaceutical industry Hollow promises or real benefit Mutat. Res., 575, 102, 2005. 

The other area is the use of microassays in toxicogenomic screening, early detection of the potential for compounds to alter gene expressions with adverse consequences (Pennie, 2000 Nuwaysir et al., 1999). 

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