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
Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180, USA.
Samsung Electro-Mechanics Co, Central R & D Institute, Suwon 443-743, South Korea.
Nat Commun. 2014 May 6;5:3739. doi: 10.1038/ncomms4739.
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.
人类肝脏中各种药物代谢酶（DMEs）的差异表达可能会导致药代动力学特征的偏差，从而引起药物毒性和/或疗效的个体间差异。在此，我们展示了“转染酶与代谢芯片”（TeamChip），它可预测潜在的代谢诱导药物或候选药物毒性。通过在互补微孔芯片中使用重组腺病毒将基因导入微柱芯片上的小型三维细胞微阵列中来制备TeamChip。该装置使用户能够在THLE-2细胞微阵列中操纵单个和多个人类代谢酶基因（如CYP3A4、CYP2D6、CYP2C9、CYP1A2、CYP2E1和UGT1A4）的表达。为了鉴定参与药物解毒的特定酶，我们在单个微阵列上以组合方式创建了84种代谢基因表达组合。因此，TeamChip平台能够以高通量方式提供评估代谢诱导毒性所需的关键信息。
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