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Toxicogenomics, Drug Discovery, and the Pathologist
Gary A. Boorman
Laboratory for Experimental Pathology, Environmental Toxicology Program, NIEHS, PO Box 12233, 111 TW Alexander Drive, Research Triangle Park, NC 27709
Steven P. Anderson
GlaxoSmithKline (GSK), 5 Moore Drive, Research Triangle Park, NC 27709
Warren M. Casey
GlaxoSmithKline (GSK), 5 Moore Drive, Research Triangle Park, NC 27709
Roger H. Brown
GlaxoSmithKline (GSK), 5 Moore Drive, Research Triangle Park, NC 27709
Lynn M. Crosby
US Environmental Protection Agency (EPA), NHEERL, Research Triangle Park, NC 27711
K. Gottschalk
GlaxoSmithKline (GSK), 5 Moore Drive, Research Triangle Park, NC 27709
Marilyn Easton
GlaxoSmithKline (GSK), 5 Moore Drive, Research Triangle Park, NC 27709
Hong Ni
GlaxoSmithKline (GSK), 5 Moore Drive, Research Triangle Park, NC 27709
Kevin T. Morgan
GlaxoSmithKline (GSK), 5 Moore Drive, Research Triangle Park, NC 27709
The field of toxicogenomics, which currently focuses on the application of large-scale differential gene expression (DGE) data to toxicology, is starting to influence drug discovery and development in the pharmaceutical industry. Toxicological pathologists, who play key roles in the development of therapeutic agents, have much to contribute to DGE studies, especially in the experimental design and interpretation phases. The intelligent application of DGE to drug discovery can reveal the potential for both desired (therapeutic) and undesired (toxic) responses. The pathologist's understanding of anatomic, physiologic, biochemical, immune, and other underlying factors that drive mechanisms of tissue responses to noxious agents turns a bewildering array of gene expression data into focused research programs. The latter process is critical for the successful application of DGE to toxicology. Pattern recognition is a useful first step, but mechanistically based DGE interpretation is where the long-term future of these new technologies lies. Pathologists trained to carry out such interpretations will become important members of the research teams needed to successfully apply these technologies to drug discovery and safety assessment. As a pathologist using DGE, you will need to learn to read DGE data in the same way you learned to read glass slides, patiently and with a desire to learn and, later, to teach. In return, you will gain a greater depth of understanding of cell and tissue function, both in health and disease.
Key Words: Differential gene expression • genomics • proteomics • rodent studies • pathology • liver • research teams • microarray • toxicology • safety assessment.
References
- Afshari CA, Nuwaysir EF, Barrett JC (1999). Application of complementary DNA microarray technology to carcinogen identification, toxicology, and drug safety evaluation. Cancer Res 59: 4759—4760.[Abstract/Free Full Text]
- Alberts B., Bray D., Lewis J., Raff M., Roberts K., Watson JD (1994). Molecular Biology of the Cell. 3rd ed. Vol.1. Garland Publishing Inc, New York, p 1294.
- Becich MJ (2000). The role of the pathologist as tissue refiner and data miner: The impact of functional genomics on the modern pathology laboratory and the critical roles of pathology informatics and bioinformatics. Mol Diagnosis 5: 287—299.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bertelsen AH, Velculescu VE (1999). High-throughput gene expression analysis using SAGE. Drug Discov Today 3: 152—159.[CrossRef][Web of Science]
- Blanchard K., DiSorbo O., Burris R., Dunn R., Farr S., Stoll R. (2000). Toxicogenomics: Understanding the use of microarrays for toxicology studies in vivo. Toxicologist 54: 195.
- Bonaldo MF, Lennon G., Soares MB (1996). Normalization and substraction: two approaches to facilitate gene discovery. Genome Res 6: 791—806.[Abstract/Free Full Text]
- Brent R. (2000). Genomic biology. Cell 1000: 169—183.
- Burczynski ME, McMillian M., Ciervo J., Li L., Parker JB, Dunn RT, Hicken S., Farr S., Johnson MD (2000). Toxicogenomic-base d discrimination of toxic mechanisms in HepG2 human hepatoma cells. Toxicol Sci 58:399—415.[Abstract/Free Full Text]
- Burgess JK, Hazelton RH (2000). New developments in the analysis of gene expression. Redox Rep 5: 63—73.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Carulli JP, Artinger M., Swain PM, Root CD, CheeL., Tullafallig C., Guerin J., Osborne M., Stein G., Lian J., Lomedico PT (1998). High throughput analysis of differential gene expression. J Cell Biochem Suppl 30/31: 286—296.
- Cho RJ, Campbell MJ, Winzeler EA, Steinmetz L., Conway A., Wodicka L., Wolfsberg TG, Gabrielian AE, Landsman D., Lockhart DJ, Morris MS, Davis RW (1998). A genome-wide transcriptional analysis of the mitotic cell cycle. Mol Cell 2: 65—73.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Claverie JM (1999). Computational methods for the indentification of differential and coordinated gene expression. Hum Molec Gen 8: 1821—1832.[Abstract/Free Full Text]
- Crosby LM, Hyder KS, DeAngelo AB, Kepler TB, Gaskill B., Benavides GR, Yoon L., Morgan KT (2000). Morphological analysis correlates with gene expression changes in cultured F344 rat mesothelial cells. Tox Appl Pharmacol 169: 205—221.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Diatchenko L., Lasu Y-F., Campbell AP, Chenchik A., Moqadam F., Huang B., Lukyanov K., Gurskaya N., Sverdlov ED, Siebert PD (1996). Suppressive subtractive hybridization: A method for generating differentially regulated of tissue-specific cDNA probes and libraries. Proc Natl Acad Sci USA 93: 6025—6030.[Abstract/Free Full Text]
- Fielden MR, Zacharewski TR (2001). Challenges and limitations of gene expression profiling in mechanistic and predictive toxicology. Tox Sciences 60: 6—10.[CrossRef]
- Gibson EE, Heid CA, Williams PA (1996). A novel method for real time quantitative PCR. Genome Res. 6: 995—1001.[Abstract/Free Full Text]
- . Green CD, Simmons JF, Taillon BE, Lewin DA (2001). Open systems; panoramic views of gene expression. J Immunol Methods 250: 67—79.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hegde P., Abernathy K., Gay C., Dharap S., Gaspard R., Hughers JF, Snesrud E., Lee N., Quackenbush J. (2000). A concise guide to cDNA microarray analysis. BioTechniques 29: 548—562.[Web of Science][Medline]
[Order article via Infotrieve]
- Holstege FCP, Jennings EG, Wyrick JJ, Lee TI, Hengartner CJ, Green MR, Golub TR, Lander ES, Young RA (1998). Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95: 717—728.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hubank M., Schatz DG (1994). Identifying differences in mRNA expression by representational difference analysis of cDNA. Nucl Acids Res 22: 5640— 5648.[Abstract/Free Full Text]
- Hubank M., Schatz DG (1999). cDNA representational difference analysis: A sensitive and flexible method for identification of differentially expressed genes. Methods Enzymol 303: 325—349.[Web of Science][Medline]
[Order article via Infotrieve]
- Hughes TR, Marton MJ, Jones AR, Roberts CF, Stoughton R., Armour CD, Bennett HA, Coffey E., Dai H., He YD, Kidd MJ, King AM, Meyer MR, Slade D., Lum PY, Stepaniants SB, Shoemaker DD, Gachotte D., Chakraburtty A., Simon J., Bard M., Friend SH (2000). Functional discovery via a compendium of expression profiles. Cell 102: 109— 126.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ishi M., Hashimoto SI, Tsutsumi S., Wada Y., Matsushima K., Kodama T., Aburatani H. (2000). Direct comparison of GeneChip and SAGE on the quantitative accuracy in transcript profiling analysis. Genomics 68: 136— 143.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kaminski N. (2000). Bioinformatics—A users perspective. AmJRespir Cell Mol Biol 23: 705—711.
- Khan J., Bittner ML, Chen Y., Meltzer PS, Trent JM (1999). DNA microarray technology: The anticipated impact on the study of human disease. Biochem Biophys Acta 1423: M17—M28.[Medline]
[Order article via Infotrieve]
- Kim S., Zeller K., Dang CV, Sandgren EP, Lee LA (2001). A strategy to identify differentially expressed genes using representational difference analysis and cDNA arrays. Anal Biochem 288: 141—148.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Klevecz RR, Kauffman SA, Shymko RM (1984). Cellular clocks and oscillators. Int Rev Cytol 86: 97—128.[Web of Science][Medline]
[Order article via Infotrieve]
- Kornmann B., Preitner N., Rifat D., Fleury-Olela F., Schibler U. (2001). Analysis of circadian liver gene expression by ADDER, a highly sensitive method for the display of differentially expressed mRNAs. Nucl Acids Res 29: e51.[Abstract/Free Full Text]
- Lee MLT, Kuo FC, Whitmore GA, Sklar J. (2000). Importance of replication in microarray gene expression studies: Statistical methods and evidence from repetitive cDNA hybridizations. Proc Natl Acad Sci USA 97: 9834— 9839.[Abstract/Free Full Text]
- Liang P., Pardee AB (1992). Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 275: 967—971.[CrossRef]
- Lockhart DJ, Winzeler EA (2000). Genomics, gene expression and DNA arrays. Nature 405: 827—836.[CrossRef][Medline]
[Order article via Infotrieve]
- Madden SL, Galella EA, Zhu J., Bertelsen AH, Beaudry GA (1997). SAGE transcript profiles for p-53-dependent growth regulation. Oncogene 15: 1079—1085.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Marton MJ, DeRisi JL, Bennett HA, Iyer VR, Meyer MR, Roberts CJ, Stoughton R., Burchard J., Slade D., Dai H., Bassett DE, Hartwell LH, Brown PO, Friend SH (1998). Drug target validation and identification of secondary drug target effects using DNA microarrays. Nat Med 4: 1293— 1301.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Mathews MB, Sonenberg N., Hershey JWB (2000). Origins and principles of translational control In: Translational control of gene expression, Sonenberg N, Hershey JWB, Mathews, MB (eds). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp 1—31.
- Morgan KT, Brown HR, Benavides GR, Crosby LM, Sprenger D., Yoon L., Ni H., Easton M., Morgan D., Laskowitz D., Tyler R. (2001). Toxicogenomic s and human risk assessment. Health Environ Risk Assess (in press).
- Murray RK, Granner DK, Mayes PA, Rodwell VW (2000). Harper's Biochemistry. 25th ed, Vol 1, McGraw-Hill, New York.
- . Notterman DA, Uri A., Sierk AJ, Levine AJ (2001). Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissues examined by oligonucleotide arrays. Cancer Res 61: 3124—3130.[Abstract/Free Full Text]
- Pennie WD, Tugwood JD, Oliver GJA, Kimber I. (2000). The principles and practices of toxicogenomics: Applications and opportunities. Toxicol Sci 54: 277—283.[Free Full Text]
- Prashar Y., Weissman SM (1996). Analysis of differential gene expression by display of 3' end restriction fragments of cDNAs. Proc Nat Acad Sci USA 93: 659—663.[Abstract/Free Full Text]
- Raitio M., Lindroos K., Laukkanen M., Pastinen T., Sistonen P., Sajantila A., Syvanen AC (2001). Y-chromosomal SNPs in Finno-Ugric-speaking populations analyzed by minisequencing on microarrays. Genome Res 11: 471— 482.[Abstract/Free Full Text]
- Rashidi HH, Buehler LK (2000). Bioinformatics Basics. 2000, Boca Raton, FL: CRC Press, p 185.
- Schena M., Davis RW (1999). Genes, genomes, and chips. In: DNA microarrays: A practical approach, Schena M (ed). Oxford University Press, Oxford, UK, pp 1—16.
- Schuchhardt J., Beule D., Malik A., Wolski E., Eickhoff H., ILehrach H., Herzel H. (2000). Normalization strategies for cDNA microarrays. Nucl Acids Res 28: e47.[Abstract/Free Full Text]
- Shimkets RA, Lowe DG, Tai JT, Sehl P., Jin H., Yang R., Perdki PF, Rothberg BE, Murtha MT, Roth ME, Shenoy SG, Windemuth A., Simpson JW, Simmons JF, Daley MP, Gold SA, McKenna MP, Hillan K., Went GT, Rothberg JM (1999). Gene expression analysis by transcript profiling coupled to a gene database query. Nat Biotechnol 17: 798—803.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Smith CG (1992). The Process of Drug Discovery and Development. Boca Raton, CRC Press, p 192.
- Sugita M., Sugiura M. (1994). The existence of eukaryotic ribonucleoprotein consensus sequence-type RNA-binding proteins in a prokaryote, Synechococcus 6301. Nucl Acids Res 22: 25—31.[Abstract/Free Full Text]
- Sutcliffe JG, Foye PE, Erlander MG, Hillbush BS, Bodzin LT, Durham JT, Hasel KW (2000). TOGA: An automated parsing technology for analyzing expression of nearly all genes. Proc Natl Acad Sci USA 97: 1976— 1981.[Abstract/Free Full Text]
- Velculescu VE, Zhang L., Vogelstein B., Kinzler KW (1995). Serial analysis of gene expression. Science 270: 484—487.[Abstract/Free Full Text]
- Vidal M. (2001). A biological atlas of functional maps. Cell 104: 333—339.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Wang A., Pierce A., Judson-Kremer K., Gaddis S., Aldaz CM, Johnson DG, MacLeod MC (1999). Rapid analysis of gene expression (RAGE) facilitates universal expression profiling. Nucl Acids Res. 27: 4609—4618.[Abstract/Free Full Text]
- Warrington JA, Nair A., Mahadevappa M., Tsygansdaya M. (2000). Comparison of human adult and fetal expression and identification of 535 housekeeping/maintenance genes. Physiol Genomics 2: 143—147.[Abstract/Free Full Text]
- Zar JH (1999). Biostatistical Analysis, 4th ed. Upper Saddle River, NJ, Prentice-Hall, p 359.
- Zhang JS, Duncan EL, Chang AC, Reddel RR (1998). Differential display of mRNA. Mol Biotechnol 10: 155—165.[Web of Science][Medline]
[Order article via Infotrieve]
- Zhang L., Zhou W., Velculescu VE, Kern SE, Hruban RH, Hamilton SR, Vogelstein B., Kinzler KW (1997). Gene expression profiles in normal and cancer cells. Science 276: 1268—1272.[Abstract/Free Full Text]
Toxicologic Pathology, Vol. 30, No. 1,
15-27 (2002)
DOI: 10.1080/01926230252824671
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