Regulation of Hepatic Uptake of Drugs and Xenobiotics

描述(申请人提供)：细胞摄取是内源性化合物和外源物质，如药物和环境污染物，在细胞内引发生理、药理和毒理事件所必需的基本现象。人们可能会认为，外源物质进入肝实质细胞的机制(S)将影响肝细胞的生物转化和胆汁排泄。据推测，肝脏对有机分子的肝窦摄取有多种转运机制。这些机制包括由有机阴离子转运多肽(OATPs)介导的广泛的有机阴离子的钠非依赖性转运。Oatp正弦转运体构成了一个重要的有机阴离子转运系统，我们推测该系统将受到经典的酶诱导化学物质和胆汁酸的调节。尽管在克隆和鉴定OATP方面取得了很大进展，但人们对OATP的调控和功能了解有限。这一缺陷，再加上小鼠基因组序列的出现和大量基因敲除小鼠模型的出现，为我们提供了一个前所未有的机会来研究和了解Oatp基因的表达调控。同时，我们新开发的Oatp4缺失小鼠(第一只也是唯一一只Oatp缺失小鼠)为我们的实验室提供了一个独特的工具来检查这种重要的Oatp在体内的功能。因此，目前的建议代表了我们的计划：(1)确定Oatp基因家族在肝脏中结构性和改变表达的分子调控机制，以及(2)表征肝脏特异性转运蛋白Oatp4的体内功能。有关OATPs的表达和调控的数据，以及来自Oatp4基因缺失小鼠的功能数据，将极大地促进我们对OATPs在生理学、药理学和毒理学中的重要性的认识，最终不仅有助于科学界预测人类的药物疗效和安全性，而且有助于开发肝脏特异性药物输送。

DESCRIPTION (provided by applicant): Cellular uptake is a fundamental phenomenon required for endogenous compounds and xenobiotics, such as drugs and environmental pollutants, to elicit physiological, pharmacological, and toxicological events within the cell. One might expect that the mechanism(s) by which xenobiotics are transported into hepatic parenchymal cells will affect hepatocellular biotransformation and biliary excretion. There are numerous transport mechanisms putatively responsible for hepatic sinusoidal uptake of organic molecules. These mechanisms include sodium-independent transport of a broad range of organic anions mediated by organic anion transporting polypeptides (Oatps). The Oatp sinusoidal transporters constitute an important organic anion transport system that we postulate will be regulated by classical enzyme inducing chemicals and bile acids. Despite much progress made in cloning and identifying Oatps, there is only a limited understanding of the regulation and function of Oatps. This deficiency, coupled with the emergence of the mouse genome sequence and the availability of numerous knockout mouse models, provides us an unprecedented opportunity to study and understand the regulation of Oatp gene expression. In parallel, our newly developed Oatp4-null mouse (the first and only Oatp-null mouse) gives our laboratory a unique tool to examine functions of this important Oatp in vivo. Therefore, the current proposal represents our plans to: (1) determine the molecular regulatory mechanisms responsible for both constitutive and altered expression of the Oatp gene family in liver, and (2) characterize the in vivo function of the liver-specific transporter Oatp4. The data generated regarding the expression and regulation of Oatps, as well as functional data from our Oatp4-null mouse will greatly advance our knowledge concerning the importance of Oatps in physiology, pharmacology, and toxicology, and ultimately not only aid the scientific community in predicting drug efficacy and safety in humans, but allow the development of liver-specific drug delivery.