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3차원 세포배양 플랫폼 항암제 감수성 및 효능/독성 검사 전문 기업

3차원 세포배양 플랫폼 항암제 감수성 및 효능/독성 검사
전문 기업

논문 2017, Archives of Toxicology, Prediction of metabolism-induced hepato…

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작성자 MBD
댓글 0건 조회 1,227회 작성일 20-04-02 13:34

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Abstract : Human liver contains various oxidative and conjugative enzymes that can convert nontoxic parent compounds to toxic metabolites or, conversely, toxic parent compounds to nontoxic metabolites. Unlike primary hepatocytes, which contain myriad drug-metabolizing enzymes (DMEs) but are difficult to culture and maintain physiological levels of DMEs, immortalized hepatic cell lines used in predictive toxicity assays are easy to culture, but lack the ability to metabolize compounds. To address this limitation and predict metabolism-induced hepatotoxicity in high throughput, we developed an advanced miniaturized three-dimensional (3D) cell-culture array (DataChip 2.0) and an advanced metabolizing enzyme microarray (MetaChip 2.0). The DataChip is a functionalized micropillar chip that supports the Hep3B human hepatoma cell line in a 3D microarray format. The MetaChip is a microwell chip containing immobilized DMEs found in the human liver. As a proof of concept for generating compound metabolites in situ on the chip and rapidly assessing their toxicity, twenty-two model compounds were dispensed into the MetaChip and sandwiched with the DataChip. The IC50 values obtained from the chip platform were correlated with rat LD50 values, human Cmax values, and drug-induced liver injury (DILI) categories to predict adverse drug reactions (ADRs) in vivo. As a result, the platform had 100% sensitivity, 86% specificity, and 93% overall predictivity at optimum cutoffs of IC50 and Cmax values. Therefore, the DataChip/MetaChip platform could be used as a high-throughput, early stage, microscale alternative to conventional in vitro multi-well plate platforms and provide a rapid and inexpensive assessment of metabolism-induced toxicity at early phases of drug development.