Elferink M G L, Olinga P, Draaisma A L, Merema M T, Bauerschmidt S, Polman J, Schoonen W G, Groothuis G M M
Department of Pharmacokinetics and Drug Delivery, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands.
Toxicol Appl Pharmacol. 2008 Jun 15;229(3):300-9. doi: 10.1016/j.taap.2008.01.037. Epub 2008 Feb 15.
The microarray technology, developed for the simultaneous analysis of a large number of genes, may be useful for the detection of toxicity in an early stage of the development of new drugs. The effect of different hepatotoxins was analyzed at the gene expression level in the rat liver both in vivo and in vitro. As in vitro model system the precision-cut liver slice model was used, in which all liver cell types are present in their natural architecture. This is important since drug-induced toxicity often is a multi-cellular process involving not only hepatocytes but also other cell types such as Kupffer and stellate cells. As model toxic compounds lipopolysaccharide (LPS, inducing inflammation), paracetamol (necrosis), carbon tetrachloride (CCl(4), fibrosis and necrosis) and gliotoxin (apoptosis) were used. The aim of this study was to validate the rat liver slice system as in vitro model system for drug-induced toxicity studies. The results of the microarray studies show that the in vitro profiles of gene expression cluster per compound and incubation time, and when analyzed in a commercial gene expression database, can predict the toxicity and pathology observed in vivo. Each toxic compound induces a specific pattern of gene expression changes. In addition, some common genes were up- or down-regulated with all toxic compounds. These data show that the rat liver slice system can be an appropriate tool for the prediction of multi-cellular liver toxicity. The same experiments and analyses are currently performed for the prediction of human specific toxicity using human liver slices.
微阵列技术是为同时分析大量基因而开发的，可能有助于在新药开发的早期阶段检测毒性。在体内和体外，在大鼠肝脏的基因表达水平上分析了不同肝毒素的作用。作为体外模型系统，使用了精密肝切片模型，其中所有肝细胞类型都以其自然结构存在。这很重要，因为药物诱导的毒性通常是一个多细胞过程，不仅涉及肝细胞，还涉及其他细胞类型，如库普弗细胞和星状细胞。作为模型有毒化合物，使用了脂多糖（LPS，诱导炎症）、对乙酰氨基酚（坏死）、四氯化碳（CCl₄，纤维化和坏死）和胶霉毒素（凋亡）。本研究的目的是验证大鼠肝切片系统作为药物诱导毒性研究的体外模型系统。微阵列研究结果表明，每个化合物和孵育时间的基因表达簇的体外谱，在商业基因表达数据库中进行分析时，可以预测体内观察到的毒性和病理情况。每种有毒化合物都会诱导特定的基因表达变化模式。此外，一些共同基因在所有有毒化合物作用下均上调或下调。这些数据表明，大鼠肝切片系统可以成为预测多细胞肝毒性的合适工具。目前正在使用人肝切片进行相同的实验和分析，以预测人类特异性毒性。
