肝样细胞模型在药物肝脏代谢和毒性研究中的进展
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摘要
药物诱导肝损伤(DILI)是导致药物临床试验失败和撤市的主要原因。在临床试验前,通常采用人源化的肝样细胞筛选模型来评估药物的代谢和预测药物发生DILI的风险。目前,常用的肝细胞模型包括肝癌细胞系、永生化原代肝细胞、多能干细胞诱导分化肝细胞和直接转分化肝细胞。但这些细胞模型均不能全面重现体内肝细胞功能。为了使体外肝细胞模型更接近体内肝细胞的状态,肝细胞培养体系的作用开始受到重视。与传统的二维(2D)和三明治培养模型相比,三维(3D)培养模型和微灌流系统能够更好地模拟肝细胞的体内微环境,是目前与体内肝细胞的形态和功能最为相似的细胞模型。综述肝样细胞模型在药物肝脏代谢和毒性研究中的进展,旨在为药物临床前研究选择合适的肝样细胞模型提供参考。
Drug-induced liver injury(DILI) is a major cause of clinical trial failure and drug attrition. Before a clinical trial, humanized hepatocyte-like cell models are usually used for assessment of drug metabolism and prediction of potential DILI risk. Currently, the commonly used hepatocyte models include hepatoma cell lines, immortalized primary hepatocytes, stem cell-derived hepatocytes and directly-induced hepatocyte-like cells. However, all these hepatocyte models could not fully recapitulate the function of hepatocytes in vivo. Various in vitro hepatocyte culture systems have been developed to culture in vitro hepatocyte models as mimetics of hepatocytes in liver. Compared to 2D and sandwich culture models, 3D culture models and microchips can better simulate the in vivo microenvironment of hepatocytes, serving as the best models of hepatocyte in terms of morphology and function. The advances of hepatocyte-like cell models in the study of hepatic metabolism and toxicity of drugs have been reviewed in this paper, providing reference for appropriate selection of hepatocyte-like cell models in the preclinical studies of drugs.
Drug-induced liver injury(DILI) is a major cause of clinical trial failure and drug attrition. Before a clinical trial, humanized hepatocyte-like cell models are usually used for assessment of drug metabolism and prediction of potential DILI risk. Currently, the commonly used hepatocyte models include hepatoma cell lines, immortalized primary hepatocytes, stem cell-derived hepatocytes and directly-induced hepatocyte-like cells. However, all these hepatocyte models could not fully recapitulate the function of hepatocytes in vivo. Various in vitro hepatocyte culture systems have been developed to culture in vitro hepatocyte models as mimetics of hepatocytes in liver. Compared to 2D and sandwich culture models, 3D culture models and microchips can better simulate the in vivo microenvironment of hepatocytes, serving as the best models of hepatocyte in terms of morphology and function. The advances of hepatocyte-like cell models in the study of hepatic metabolism and toxicity of drugs have been reviewed in this paper, providing reference for appropriate selection of hepatocyte-like cell models in the preclinical studies of drugs.
引文
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