Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.
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DOI：
10.1007/s00204-013-1078-5
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发表时间：
2013-08
影响因子：
6.1
通讯作者：
Hengstler, Jan G.
中科院分区：
文献类型：
--
作者：
Godoy, Patricio;Hewitt, Nicola J.;Albrecht, Ute;Andersen, Melvin E.;Ansari, Nariman;Bhattacharya, Sudin;Bode, Johannes Georg;Bolleyn, Jennifer;Borner, Christoph;Boettger, Jan;Braeuning, Albert;Budinsky, Robert A.;Burkhardt, Britta;Cameron, Neil R.;Camussi, Giovanni;Cho, Chong-Su;Choi, Yun-Jaie;Rowlands, J. Craig;Dahmen, Uta;Damm, Georg;Dirsch, Olaf;Teresa Donato, Maria;Dong, Jian;Dooley, Steven;Drasdo, Dirk;Eakins, Rowena;Ferreira, Karine Sa;Fonsato, Valentina;Fraczek, Joanna;Gebhardt, Rolf;Gibson, Andrew;Glanemann, Matthias;Goldring, Chris E. P.;Jose Gomez-Lechon, Maria;Groothuis, Geny M. M.;Gustavsson, Lena;Guyot, Christelle;Hallifax, David;Hammad, Seddik;Hayward, Adam;Haeussinger, Dieter;Hellerbrand, Claus;Hewitt, Philip;Hoehme, Stefan;Holzhuetter, Hermann-Georg;Houston, J. Brian;Hrach, Jens;Ito, Kiyomi;Jaeschke, Hartmut;Keitel, Verena;Kelm, Jens M.;Park, B. Kevin;Kordes, Claus;Kullak-Ublick, Gerd A.;LeCluyse, Edward L.;Lu, Peng;Luebke-Wheeler, Jennifer;Lutz, Anna;Maltman, Daniel J.;Matz-Soja, Madlen;McMullen, Patrick;Merfort, Irmgard;Messner, Simon;Meyer, Christoph;Mwinyi, Jessica;Naisbitt, Dean J.;Nussler, Andreas K.;Olinga, Peter;Pampaloni, Francesco;Pi, Jingbo;Pluta, Linda;Przyborski, Stefan A.;Ramachandran, Anup;Rogiers, Vera;Rowe, Cliff;Schelcher, Celine;Schmich, Kathrin;Schwarz, Michael;Singh, Bijay;Stelzer, Ernst H. K.;Stieger, Bruno;Stoeber, Regina;Sugiyama, Yuichi;Tetta, Ciro;Thasler, Wolfgang E.;Vanhaecke, Tamara;Vinken, Mathieu;Weiss, Thomas S.;Widera, Agata;Woods, Courtney G.;Xu, Jinghai James;Yarborough, Kathy M.;Hengstler, Jan G.
关键词：
本文综述了在肝功能和肝毒性方面的最重要进展，并分析了哪些机制可以在体外研究。在巢状、分带小叶的复杂结构中，肝脏由大约80%的肝细胞和20%的非实质细胞组成，后者处于可显著加重初始损伤的继发性阶段。肝毒性和肝脏代谢是由一系列核受体（包括PXR、CAR、HNF-4α、FXR、LXR、SHP、VDR和PPAR）和信号通路控制的。当分离肝细胞时，一些通路被激活，如RAS/MEK/ERK通路，而另一些通路被沉默（如HNF-4α），导致数百个基因上调和下调。了解这些变化对于正确解释体外数据至关重要。总结了目前最有用的体外肝脏系统的可能性和局限性，包括三维培养技术、与非实质细胞共培养技术、肝球、精确切割肝片和离体灌注肝。还讨论了肝癌、干细胞和iPS细胞衍生的肝细胞样细胞与真实肝细胞的相似程度。最后，总结了目前在制药工业中使用的体外肝脏和数学建模系统的现状，重点是药物代谢、预测清除、药物相互作用、转运体研究和肝毒性。一个关键信息是，尽管我们对体外系统充满热情，但我们绝不能忽视体内的情况。虽然肝细胞已经分离了几十年，但寻找相关的替代系统才刚刚开始。本文的在线版本（doi:10.1007/s00204-013-1078-5）包含补充材料，可供授权用户使用。
This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun. The online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.
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影响因子：
3.3
作者：
ADAMS, RM;WANG, M;LEDLEY, FD
通讯作者：
LEDLEY, FD
影响因子：
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作者：
Alvarez-Sanchez, Ruben;Montavon, Francois;Paehler, Axel
通讯作者：
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影响因子：
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作者：
Allen, JW;Khetani, SR;Bhatia, SN
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影响因子：
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作者：
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通讯作者：
Gonzalez, FJ
DOI：
10.1124/jpet.110.176321
发表时间：
2011-04-01
影响因子：
3.5
作者：
Agarwal, Rakhee;MacMillan-Crow, Lee Ann;Hinson, Jack A.
通讯作者：
Hinson, Jack A.