Development of Cell Culture Analog Systems for Use With Pharmokinetic Models

这项工作的最终目标是开发技术，更好地评估化学品对人类的潜在毒性。目前，对化学品进行毒理学和药理学测试需要大量的动物。从整个动物研究中获得的数据很难跨物种线准确外推，也很难在低剂量下产生影响。基本的代谢相互作用很难监测。出于经济和伦理两方面的考虑，减少这种试验中使用的动物数量是可取的。生物技术和细胞培养的进步为开发替代方法提供了机会，这些方法既可以产生更好的数据，又可以减少对动物的使用。这项工作将结合药代动力学模型和体外细胞培养技术来构建整个动物的直接物理模拟。这一概念将通过构建一个小鼠类似物来测试-使用来自肝脏的两种类型的肺细胞和肝细胞。可以直接观察到外源物质生物转化的分子水平机制。进一步将机械学信息纳入药动模型将允许对观测进行外推。关于哪种细胞色素负责萘的生物激活以及哪种细胞类型主要负责其激活的争议将被解决。

The ultimate goal of this work is to develop techniques to better evaluate the potential toxicity of chemicals to humans. Currently, toxicological and pharmacological testing of chemicals requires large numbers of animals. Data obtained from whole animal studies are difficult to accurately extrapolate across species lines and to effects at low doses. Basic metabolic interactions are difficult to monitor. On both economic and ethical grounds it is desirable to reduce the number of animals utilized in such testing. Advances in biotechnology and cell culture present an opportunity to develop alternative methods that can yield both better data and reduced use of animals. This work will combine pharmokinetic models and in vitro cell culture techniques to construct a direct physical analog of the whole animal. This concept will be tested by constructing a mouse analog - using two types of lung cells and hepatocytes from the liver. Direct observations can be made of molecular level mechanisms for biotransformations of xenobiotics. Further incorporation of mechanistic information into the pharmokinetic model will allow extrapolation of observations. Controversies on which cytochromes are responsible for bioactivation of napthalene and on which cell types are primarily responsible for its activation will be addressed.