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

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...

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Bibliographic Details
Published in:Nature communications 2014-05, Vol.5 (1), p.3739-3739, Article 3739
Main Authors: Kwon, Seok Joon, Lee, Dong Woo, Shah, Dhiral A., Ku, Bosung, Jeon, Sang Youl, Solanki, Kusum, Ryan, Jessica D., Clark, Douglas S., Dordick, Jonathan S., Lee, Moo-Yeal
Format: Article
Language:English
Subjects:
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Cell Line
Cytochrome P-450 Enzyme System - metabolism
Gene Expression
High-Throughput Screening Assays - methods
Humanities and Social Sciences
Humans
Liver - enzymology
Liver - metabolism
multidisciplinary
Science
Science (multidisciplinary)
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Summary: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. Current tools to test drug metabolism and toxicity in the liver are mainly based on time-consuming traditional cell culture methods. Here Kwon et al. report a high-throughput system employing cells cultured on micropillars that can be transfected with combinations of drug-metabolizing enzymes.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms4739