| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Pharmacology Department
2 Drug Metabolism Department, Merck Research Laboratories, West Point, Pennsylvania 19486
Oligonucleotide DNA microarrays were investigated for utility in measuring global expression profiles of drug metabolism genes. This study was performed to investigate the feasibility of using microarray technology to minimize the long, expensive process of testing drug candidates for safety in animals. In an evaluation of hybridization specificity, microarray technology from Affymetrix distinguished genes up to a threshold of 
90% DNA identity. Oligonucleotides representing human cytochrome P-450 gene CYP3A5 showed heterologous hybridization to CYP3A4 and CYP3A7 RNAs. These genes could be clearly distinguished by selecting a subset of oligonucleotides that hybridized selectively to CYP3A5. Further validation of the technology was performed by measuring gene expression profiles in livers of rats treated with vehicle, 3-methylcholanthrene (3MC), phenobarbital, dexamethasone, or clofibrate and by confirming data for six genes using quantitative RT-PCR. Responses of drug metabolism genes, including CYPs, epoxide hydrolases (EHs), UDP-glucuronosyl transferases (UGTs), glutathione sulfotransferases (GSTs), sulfotransferases (STs), drug transporter genes, and peroxisomal genes, to these well-studied compounds agreed well with, and extended, published observations. Additional gene regulatory responses were noted that characterize metabolic effects or stress responses to these compounds. Thus microarray technology can provide a facile overview of gene expression responses relevant to drug metabolism and toxicology.
DNA microarray; drug metabolism; gene regulation; cytochrome P-450
This article has been cited by other articles:
|
|
 |
|
  D. M. Nelson, V. Bhaskaran, W. R. Foster, and L. D. Lehman-McKeeman p53-Independent Induction of Rat Hepatic Mdm2 following Administration of Phenobarbital and Pregnenolone 16{alpha}-Carbonitrile Toxicol. Sci., December 1, 2006; 94(2): 272 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. J. Troost, R.-J. M. Brummer, G. R. M. M. Haenen, A. Bast, R. I. van Haaften, C. T. Evelo, and W. H. M. Saris Gene expression in human small intestinal mucosa in vivo is mediated by iron-induced oxidative stress Physiol Genomics, April 11, 2006; 25(2): 242 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Troost, R.-J. M. Brummer, G. R. M. M. Haenen, A. Bast, R. I. van Haaften, C. T. Evelo, and W. H. M. Saris Gene expression in human small intestinal mucosa in vivo is mediated by iron-induced oxidative stress Physiol Genomics, April 11, 2006; 25(2): 242 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ekins, S. Andreyev, A. Ryabov, E. Kirillov, E. A. Rakhmatulin, S. Sorokina, A. Bugrim, and T. Nikolskaya A COMBINED APPROACH TO DRUG METABOLISM AND TOXICITY ASSESSMENT Drug Metab. Dispos., March 1, 2006; 34(3): 495 - 503. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Masson, L. Lagrost, A. Athias, P. Gambert, C. Brimer-Cline, L. Lan, J. D. Schuetz, E. G. Schuetz, and M. Assem Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid-Mediated Changes in Plasma Lipoprotein Profile Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2164 - 2169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tian, L. Cao, Y. Tan, S. Williams, L. Chen, T. Matray, A. Chenna, S. Moore, V. Hernandez, V. Xiao, et al. Multiplex mRNA assay using electrophoretic tags for high-throughput gene expression analysis Nucleic Acids Res., September 8, 2004; 32(16): e126 - e126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Handschin and U. A. Meyer Induction of Drug Metabolism: The Role of Nuclear Receptors Pharmacol. Rev., December 1, 2003; 55(4): 649 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. de Longueville, F. A. Atienzar, L. Marcq, S. Dufrane, S. Evrard, L. Wouters, F. Leroux, V. Bertholet, B. Gerin, R. Whomsley, et al. Use of a Low-Density Microarray for Studying Gene Expression Patterns Induced by Hepatotoxicants on Primary Cultures of Rat Hepatocytes Toxicol. Sci., October 1, 2003; 75(2): 378 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Jessen, J. S. Mullins, A. de Peyster, and G. J. Stevens Assessment of Hepatocytes and Liver Slices as in Vitro Test Systems to Predict in Vivo Gene Expression Toxicol. Sci., September 1, 2003; 75(1): 208 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Tolstrup, P. S. Nielsen, J. G. Kolberg, A. M. Frankel, H. Vissing, and S. Kauppinen OligoDesign: optimal design of LNA (locked nucleic acid) oligonucleotide capture probes for gene expression profiling Nucleic Acids Res., July 1, 2003; 31(13): 3758 - 3762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Sarang, T. Yoshida, R. Cadet, A. S. Valeras, R. V. Jensen, and S. R. Gullans Discovery of molecular mechanisms of neuroprotection using cell-based bioassays and oligonucleotide arrays Physiol Genomics, October 29, 2002; 11(2): 45 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, B. Chanas, and B. I. Ghanayem Cytochrome P450 2E1 (CYP2E1) is Essential for Acrylonitrile Metabolism to Cyanide: Comparative Studies Using CYP2E1-Null and Wild-Type Mice Drug Metab. Dispos., August 1, 2002; 30(8): 911 - 917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. T. Morgan Gene Expression Analysis Reveals Chemical-Specific Profiles Toxicol. Sci., June 1, 2002; 67(2): 155 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Arcellana-Panlilio and S. M. Robbins Cutting-edge technology: I. Global gene expression profiling using DNA microarrays Am J Physiol Gastrointest Liver Physiol, March 1, 2002; 282(3): G397 - G402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. J. Dzau and S. Glueck Physiological Genomics: Who we are and where we're going Physiol Genomics, December 21, 2001; 7(2): 65 - 67. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
