INSERM 522-EA MDC, Hopital Pontchaillou and Université de Rennes I, 35033 Rennes Cedex, France.
Toxicology. 2010 Mar 30;270(1):3-9. doi: 10.1016/j.tox.2009.09.019. Epub 2009 Oct 6.
Better prediction of safety risk and understanding of mechanism of action of drug candidates remain a major challenge in order to prevent late stage attrition. Continuous efforts are made to improve and develop new models, especially in some areas such as hepatotoxicity. Besides primary hepatocytes and transformed liver cell lines, stem cells either isolated from embryos or adult tissues or obtained by reprogramming somatic cells are emerging as a new potential source of unlimited numbers of hepatocytes. Presently, only hepatocyte-like cells expressing low levels of liver-specific markers, especially drug metabolizing and detoxifying enzymes, are usually obtained, making them still unsuitable as metabolically competent cells for toxicity studies. The only exceptions are some hepatoma cell lines, particularly the HepaRG cell line that can differentiate from a bipotent progenitor stage to attain the functional capacity of normal adult hepatocytes in primary culture without losing the indefinite growth property of transformed cells. Since the research field on stem cells is growing fast marked advances might be expected in the next future.
为了防止药物研发后期淘汰，更好地预测安全性风险和了解候选药物的作用机制仍然是一个主要挑战。人们一直在努力改进和开发新的模型，特别是在一些领域，如肝毒性。除了原代肝细胞和转化的肝细胞系外，从胚胎或成人组织中分离出的干细胞，或通过重编程体细胞获得的干细胞，正成为一种新的、具有无限数量肝细胞潜力的潜在来源。目前，通常只能获得表达低水平肝特异性标志物的肝样细胞，特别是药物代谢和解毒酶，这使得它们仍然不适合作为毒理学研究的代谢功能细胞。唯一的例外是一些肝癌细胞系，特别是 HepaRG 细胞系，它可以从双潜能祖细胞阶段分化，在原代培养中获得正常成年肝细胞的功能能力，而不会失去转化细胞的无限生长特性。由于干细胞的研究领域发展迅速，预计在未来的一段时间内将会取得显著进展。
