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High-throughput and combinatorial gene expression on a chip for metabolism-induced toxicology screening.

Abstract
Differential expression of various drug-metabolizing enzymes (DMEs) in the human liver may cause deviations of pharmacokinetic profiles, resulting in interindividual variability of drug toxicity and/or efficacy. Here, we present the 'Transfected Enzyme and Metabolism Chip' (TeamChip), which predicts potential metabolism-induced drug or drug-candidate toxicity. The TeamChip is prepared by delivering genes into miniaturized three-dimensional cellular microarrays on a micropillar chip using recombinant adenoviruses in a complementary microwell chip. The device enables users to manipulate the expression of individual and multiple human metabolizing-enzyme genes (such as CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2E1 and UGT1A4) in THLE-2 cell microarrays. To identify specific enzymes involved in drug detoxification, we created 84 combinations of metabolic-gene expressions in a combinatorial fashion on a single microarray. Thus, the TeamChip platform can provide critical information necessary for evaluating metabolism-induced toxicity in a high-throughput manner.
AuthorsSeok Joon Kwon, Dong Woo Lee, Dhiral A Shah, Bosung Ku, Sang Youl Jeon, Kusum Solanki, Jessica D Ryan, Douglas S Clark, Jonathan S Dordick, Moo-Yeal Lee
JournalNature communications (Nat Commun) Vol. 5 Pg. 3739 (May 06 2014) ISSN: 2041-1723 [Electronic] England
PMID24799042 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Cytochrome P-450 Enzyme System
Topics
  • Cell Line
  • Cytochrome P-450 Enzyme System (metabolism)
  • Gene Expression
  • High-Throughput Screening Assays (methods)
  • Humans
  • Liver (enzymology, metabolism)

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