Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-51 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
Drug Metab Dispos. 2012 Jan;40(1):169-77. doi: 10.1124/dmd.111.041137. Epub 2011 Oct 18.
Primary hepatocytes have been used in drug development for the evaluation of hepatotoxicity of candidate compounds. However, the rapid depression of their hepatic characters in vitro must be improved to predict toxicity with higher accuracy. We have hypothesized that a well organized tissue construct that includes nonparenchymal cells and appropriate scaffold material(s) could overcome this difficulty by remediating the viability and physiological function of primary hepatocytes. In this study, we constructed an in vitro liver tissue model, consisting of mouse primary hepatocytes assembling around an endothelial cell network on Engelbreth-Holm-Swarm gel, and examined its response to acetaminophen treatment. The increase in lactate dehydrogenase release after the exposure to acetaminophen was induced earlier in the liver tissue model than in monolayer hepatocytes alone, suggesting that the tissue model was more sensitive to an acetaminophen-induced toxicity. On the basis of our results, we conclude that liver tissue models of this kind may enhance the responses of hepatocytes against xenobiotics via the maintenance of hepatic genes and functions such as cytochrome P450s. These findings will contribute to the development of more accurate systems for evaluating hepatotoxicity.
原代肝细胞已被用于候选化合物肝毒性的药物开发评估。然而，其在体外的肝特性迅速下降，必须加以改善，以提高预测毒性的准确性。我们假设，一种组织构建良好的结构，包括非实质细胞和适当的支架材料，可以通过改善原代肝细胞的活力和生理功能来克服这一困难。在这项研究中，我们构建了一个体外肝脏组织模型，由围绕内皮细胞网络组装的小鼠原代肝细胞组成，在 Engelbreth-Holm-Swarm 凝胶上，并检测了它对乙酰氨基酚处理的反应。与单层肝细胞相比，暴露于对乙酰氨基酚后，组织模型中乳酸脱氢酶的释放增加更早，这表明该组织模型对乙酰氨基酚诱导的毒性更敏感。基于我们的结果，我们得出结论，这种肝脏组织模型可以通过维持细胞色素 P450 等肝基因和功能来增强肝细胞对异生物的反应。这些发现将有助于开发更准确的肝毒性评估系统。
