Abstract
Many drugs or xenobiotics can induce specific or nonspecific cellular signal transduction events that activate various physiologic and pharmacologic responses including homeostasis, proliferation, differentiation, apoptosis, and necrosis. To minimize the insults caused by these xenobiotics, tissues and organs are equipped with protective mechanisms that either pump drugs out of the cells (e.g., the multidrug-resistant, mdr, family of proteins) or increase the level of detoxifying enzymes such as phase I and II drug-metabolizing enzymes (DMEs), after exposure to xenobiotics. This review discusses the molecular analysis of pharmaco- or toxicogenomic gene expression profiles following exposure to cancer chemotherapeutic and chemopreventive agents. We present the development of DNA microarray technology and its use in expression profiling of possible signal transduction events elicited by these compounds, and its potential future applications in drug discovery and development in the pharmaceutical industry.
Similar content being viewed by others
REFERENCES
E. S. Lander et al. Initial sequencing and analysis of the human genome. Nature 409:860–921 (2001).
J. C. Venter et al. The sequence of the human genome. Science 291:1304–1351 (2001).
F. Antequera and A. Bird. Number of CpG islands and genes in human and mouse. Proc. Natl. Acad. Sci. USA 90:11995–11999 (1993).
D. Zhuo, W. D. Zhao, F. A. Wright, H. Y. Yang, J. P. Wang, R. Sears, T. Baer, D. H. Kwon, D. Gordon, S. Gibbs, D. Dai, Q. Yang, J. Spitzner, R. Krahe, D. Stredney, A. Stutz, and B. Yuan. Assembly, annotation, and integration of UNIGENE clusters into the human genome draft. Genome Res. 11:904–918 (2001).
M. Schena, D. Shalon, R. W. Davis, and P. O. Brown. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270:467–470 (1995).
R. J. Lipshutz, S. P. Fodor, T. R. Gingeras, and D. J. Lockhart. High density synthetic oligonucleotide arrays. Nature Genet. 21: 20–24 (1999).
J. G. Hacia and F. S. Collins. Mutational analysis using oligonucleotide microarrays. J Med. Genet. 36:730–736 (1999).
C. A. Afshari, E. F. Nuwaysir, and J. C. Barrett. Application of complementary DNA microarray technology to carcinogen identification, toxicology, and drug safety evaluation. Cancer Res. 59: 4759–4760 (1999).
K. Kudoh, M. Ramanna, R. Ravatn, A. G. Elkahloun, M. L. Bittner, P. S. Meltzer, J. M. Trent, W. S. Dalton, and K. V. Chin. Monitoring the expression profiles of doxorubicin-induced and doxorubicin-resistant cancer cells by cDNA microarray. Cancer Res. 60:4161–4166 (2000).
D. W. Voehringer, D. L. Hirschberg, J. Xiao, Q. Lu, M. Roederer, C. B. Lock, L. A. Herzenberg, and L. Steinman. Gene microarray identification of redox and mitochondrial elements that control resistance or sensitivity to apoptosis. Proc. Natl. Acad. Sci. USA 97:2680–2685 (2000).
X. Zheng, R. Ravatn, Y. Lin, W. Shih, A. Rabson, R. Strair, E. Huberman, A. Conney, and K.-V. Chin. Analysis of the mechanisms of TPA induced differentiation in HL-60 cells by expression profiling with DNA microarray. Nucleic Acid Res. 30:4489–4499 (2002).
A. N. Kong, R. Yu, V. Hebbar, C. Chen, E. Owuor, R. Hu, R. Ee, and S. Mandlekar. Signal transduction events elicited by cancer prevention compounds. Mutat. Res. 480-481:231–241 (2001).
M. B. Eisen, P. T. Spellman, P. O. Brown, and D. Botstein. Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. USA 95:14863–14868 (1998).
T. H. Rushmore and A.-N. T. Kong. Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. Curr. Drug Metab. 3:481–490 (2002).
S. J. Duthie and M. H. Grant. The toxicity of menadione and mitozantrone in human liver-derived Hep G2 hepatoma cells. Biochem. Pharmacol. 38:1247–1255 (1989).
Y. Mao, S. D. Desai, C. Y. Ting, J. Hwang, and L. F. Liu. 26 S proteasome-mediated degradation of topoisomerase II cleavable complexes. J. Biol, Chem. 276:40652–40658 (2001).
L. J. van 't Veer, H. Dai, M. J. van de Vijver, Y. D. He, A. A. Hart, M. Mao, H. L. Peterse, K. van der Kooy, M. J. Marton, A. T. Witteveen, G. J. Schreiber, R. M. Kerkhoven, C. Roberts, P. S. Linsley, R. Bernards, and S. H. Friend. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536 (2002).
E. J. Yeoh, M. E. Ross, S. A. Shurtleff, W. K. Williams, D. Patel, R. Mahfouz, F. G. Behm, S. C. Raimondi, M. V. Relling, A. Patel, C. Cheng, D. Campana, D. Wilkins, X. Zhou, J. Li, H. Liu, C. H. Pui, W. E. Evans, C. Naeve, L. Wong, and J. R. Downing. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1:133–143 (2002).
A. Rosenwald, G. Wright, W. C. Chan, J. M. Connors, E. Campo, R. I. Fisher, R. D. Gascoyne, H. K. Muller-Hermelink, E. B. Smeland, J. M. Giltnane, E. M. Hurt, H. Zhao, L. Averett, L. Yang, W. H. Wilson, E. S. Jaffe, R. Simon, R. D. Klausner, J. Powell, P. L. Duffey, D. L. Longo, T. C. Greiner, D. D. Weisenburger, W. G. Sanger, B. J. Dave, J. C. Lynch, J. Vose, J. O. Armitage, E. Montserrat, A. Lopez-Guillermo, T. M. Grogan, T. P. Miller, M. LeBlanc, G. Ott, S. Kvaloy, J. Delabie, H. Holte, P. Krajci, T. Stokke, and L. M. Staudt. The use of molecular profiling to predict survival after chemotherapy for diffuse large-Bcell lymphoma. N. Engl. J. Med. 346:1937–1947 (2002).
D.G. Beer, S. L. Kardia, C. C. Huang, T. L. Giordano, A. M. Levin, D. E. Misek, L. Lin, G. Chen, T. G. Gharib, D.G. Thomas, M. L.Lizyness, R. Kuick, S. Hayasaka, J. M. Taylor, M. D. Iannettoni, M. B. Orringer, and S. Hanash. Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nature Med. (epub) doi:10.1038/nm733 (2002).
R. Yu, C. Chen, Y. Y. Mo, V. Hebbar, E. D. Owuor, T. H. Tan, and A. N. Kong. Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. J. Biol. Chem. 275: 39907–39913 (2000).
H. C. Huang, T. Nguyen, and C. B. Pickett. Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc. Natl. Acad. Sci. USA 97:12475–12480 (2000).
J. M. Lee, J. M. Hanson, W. A. Chu, and J. A. Johnson. Phosphatidylinositol 3-kinase, not extracellular signal-regulated kinase, regulates activation of the antioxidant-responsive element in IMR-32 human neuroblastoma cells. J. Biol. Chem. 276:20011–20016 (2001).
J. Y. Chan, X. L. Han, and Y. W. Kan. Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. Proc. Natl. Acad. Sci. USA 90:11371–11375 (1993).
R. Venugopal and A. K. Jaiswal. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc. Natl. Acad. Sci. USA 93:14960–14965 (1996).
J. Y. Chan, X. L. Han, and Y. W. Kan. Isolation of cDNA encoding the human NF-E2 protein. Proc. Natl. Acad. Sci. USA 90:11366–11370 (1993).
M. G. Marini, K. Chan, L. Casula, Y. W. Kan, A. Cao, and P. Moi. hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2. J. Biol. Chem. 272:16490–16497 (1997).
A. N. Kong, E. Owuor, R. Yu, V. Hebbar, C. Chen, R. Hu, and S. Mandlekar. Induction of xenobiotic enzymes by the map kinase pathway and the antioxidant or electrophile response element (ARE/EpRE). Drug Metab. Rev. 33:255–271 (2001).
K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, K. Igarashi, J. D. Engel, and M. Yamamoto. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13:76–86 (1999).
R. Hu, C. Chen, V. Hebbar, and A.-N. T. Kong. cDNA microarray analysis of sulforaphane and (-)-epigallocatechin-3-gallateinduced gene expression profiles. AAPS Pharm. Sci. Suppl. 3: 2333 (2001).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Chin, KV., Kong, AN.T. Application of DNA Microarrays in Pharmacogenomics and Toxicogenomics. Pharm Res 19, 1773–1778 (2002). https://doi.org/10.1023/A:1021425004264
Issue Date:
DOI: https://doi.org/10.1023/A:1021425004264