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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance
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Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

机译：氧气介导的原代肝细胞代谢增强，功能极化，基因表达和药物清除

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摘要

The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/ drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenviron-ment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an R~2 of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures.
机译：肝脏由于其丰富的I / II期代谢酶水平，是异种生物化合物代谢的主要场所。随着药物开发成本增加到每药超过4亿美元，迫切需要开发严格的肝代谢模型以进行临床前药物清除和肝毒性筛查。在这里，我们提出了一种微环境，其中原代人类和大鼠的肝细胞维持了高水平的代谢能力，而没有很长的适应期。我们证明肝细胞和内皮细胞在无血清培养基中接种于95％氧气下的共培养可保持功能性心尖和基础极性，高水平的细胞色素P450活性以及与新鲜分离的肝细胞同等的基因表达谱。这些含氧共培养物显示出显着的预测快速清除和缓慢清除药物的体内药物清除率的能力，R〜2为0.92。此外，由于含氧共培养物的代谢功能在一夜之间稳定下来，因此可以在其他培养方法之前数天甚至数周进行临床前测试，从而显着减少了相关的人工和成本。这些结果可以很容易地扩展到其他培养结构，包括三维培养，生物反应器研究以及微加工共培养。

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  • 作者

    Srivatsan Kidambi; Rubin S. Yarmush; Eric Novik; Piyun Chao; Martin L. Yarmush; Yaakov Nahmias;

  • 作者单位

    Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02111;

    Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02111;

    HμREL Corporation, Beverly Hills, CA 90211;

    HμREL Corporation, Beverly Hills, CA 90211;

    Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02111;

    Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02111 The Selim and Rachel Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    drug discovery; liver metabolism; tissue engineering;

    机译：药物发现;肝脏代谢组织工程;

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