High Throughput Liver Toxicity Screening

高通量肝脏毒性筛查

• 批准号: 6545279
• 负责人: JAMES Henry KELLY
• 金额: $ 23.5万
• 依托单位: AMPHIOXUS CELL TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6545279
• 关键词: adenosine triphosphate; cell proliferation; cysteine endopeptidases; cytochrome P450; drug metabolism; drug screening /evaluation; hepatotoxin; high throughput technology; lactate dehydrogenases; liver pharmacology; nonsteroidal antiinflammatory agent; technology /technique development; tissue /cell culture; toxicant screening

DESCRIPTION (provided by applicant): Liver toxicity is the most common cause for failure in new drug development except for efficacy failures. To address this problem, we have developed a series of tests measuring basic events in cellular toxicity using a patented human liver cell line: proliferation. ATP content, caspase activation and lactate dehydrogenase release. In addition, we have employed several tests that are specifically related to drug metabolism in the liver: cyplAl/1A2 induction cyp3A4 induction and P-glycoprotein inhibition. When used in combination, these seven tests give a broad and rich picture of compound interaction in the liver. They are fast, rugged and inexpensive. In phase I of this project, we propose to screen a small (640) library of randomly chosen compounds and a group of structurally related compounds (NSAIDS) to examine the breadth of response of this system. If the results of this preliminary screening are satisfactory, in phase II we would propose to screen a large series of random compounds (approximately 30,000) and smaller series of structurally related compounds with the idea of building a database of toxicity that could be used to guide new drug synthesis. PROPOSED COMMERCIAL APPLICATIONS: ACTIVTox, our human liver toxicity and metabolism system, is based on a patented human liver cell line and proprietary medium and cell culture conditions. We expected to sell kits consisting of ready to use plates filled with cells, medium and reagents to carry out the individual test on a high throughput basis. The market for such a human toxicity system exceeds $25 million annually.

描述（由申请人提供）：肝毒性是新药开发失败的最常见原因，疗效失败除外。为了解决这个问题，我们开发了一系列测试，使用专利的人肝细胞系测量细胞毒性的基本事件：增殖。ATP含量、半胱天冬酶活化和乳酸脱氢酶释放。此外，我们采用了几种与肝脏中药物代谢特别相关的测试：cyplAl/1A 2诱导、cyp 3A 4诱导和P-糖蛋白抑制。当组合使用时，这七种测试给出了肝脏中化合物相互作用的广泛而丰富的图片。它们速度快，坚固耐用，价格低廉。在这个项目的第一阶段，我们建议筛选一个小的（640）随机选择的化合物和一组结构相关的化合物（NSAIDS）库，以检查该系统的响应宽度。如果初步筛选的结果令人满意，在第二阶段，我们将建议筛选大量随机化合物（约30，000种）和较小系列的结构相关化合物，以建立一个可用于指导新药合成的毒性数据库。 拟议的商业应用： ACTIVTox是我们的人类肝脏毒性和代谢系统，基于专利的人类肝脏细胞系和专有培养基和细胞培养条件。我们希望出售的试剂盒包括即用型板，其中装有细胞、培养基和试剂，以高通量的方式进行个体检测。这种人体毒性系统的市场每年超过2500万美元。