In Vivo Kinetic Biomarkers of Hepatic Toxicity

肝毒性的体内动力学生物标志物

• 批准号: 6841852
• 负责人: SCOTT M TURNER
• 金额: $ 24.41万
• 依托单位: KINEMED, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841852
• 关键词: biomarker; cell proliferation; cytochrome c; deuterium oxide; drug administration rate /duration; fibrogenesis; gene expression profiling; hepatotoxin; hydroxyproline; laboratory mouse; laboratory rat; liver cells; liver metabolism; liver toxic disorder; microarray technology; mitochondria; proliferating cell nuclear antigen; technology /technique development; toxicant screening

DESCRIPTION (provided by applicant): A flood of drug candidates increases the need for novel assays to measure liver toxicity. We have developed methods for quantifying multiple metabolic fluxes in vivo using 2H2O labeling. Here we propose to validate this approach as a toxicity screen. We will test 14 hepatotoxins with diverse mechanisms of action for their ability to alter liver cell turnover (hepatocytes, endothelial cells, total liver cells), mitochondrial biogenesis, and collagen synthesis as markers of liver damage and homeostasis. We will correlate these measurements with changes in static markers of cell division; morphology of sinusoidal endothelial cells; mitochondrial cytochrome c; and collagen deposition, respectively. We hypothesize that toxic concentrations of drugs known to affect the latter phenotypes will strongly modulate fluxes in the underlying metabolic pathways. We will compare static markers and 2H labeling for their ability to detect drug-induced subclinical changes at limiting doses/exposure times and to reveal novel toxic activities. Finally, we will screen for gene expression patterns that predict end organ damage as detected by our test. This work will provide a solid foundation for regulatory approval of our toxicity screen, for extension of our work to other end organs, and for use in humans.

描述（由申请人提供）： 大量的候选药物增加了对测量肝毒性的新测定方法的需求。我们开发了使用 2H2O 标记量化体内多种代谢通量的方法。在这里，我们建议验证这种方法作为毒性筛查的效果。我们将测试 14 种具有不同作用机制的肝毒素，看看它们改变肝细胞更新（肝细胞、内皮细胞、总肝细胞）、线粒体生物发生和胶原蛋白合成的能力，作为肝损伤和体内平衡的标志。我们将把这些测量结果与细胞分裂的静态标记物的变化联系起来；肝窦内皮细胞的形态；线粒体细胞色素c；和胶原沉积，分别。我们假设已知影响后一种表型的药物的毒性浓度将强烈调节潜在代谢途径的通量。我们将比较静态标记物和 2H 标记物在有限剂量/暴露时间下检测药物引起的亚临床变化并揭示新毒性活性的能力。最后，我们将筛选基因表达模式，预测我们的测试检测到的终末器官损伤。这项工作将为我们的毒性筛选的监管批准、将我们的工作扩展到其他终末器官以及用于人体提供坚实的基础。