REGULATION OF HEPATIC UPTAKE OF DRUGS AND XENOBIOTICS

描述(逐字摘自申请者摘要)：细胞摄取 外源生物是内源生物化学物质所必需的基本现象， 药物，和化学物质，以引发任何数量的生化， 细胞内的药理和/或毒理事件。似乎 直觉地认为，外来物进入人体的机制(S) 肝实质细胞会影响肝细胞 发生生物转化和胆汁排泄。传输机制是 推测是肝脏摄取有机分子的原因。有机食品 阴离子转运多肽Oatp1和Oatp2介导钠非依赖性 广泛的有机阴离子(如胆汁酸、雌激素)的运输 结合物、白三烯结合物、未结合胆红素和心脏 糖苷)转化为肝细胞。Oatp1和Oatp2正弦转运蛋白 构成了一个重要的运输系统，我们假定要受其监管 AGE和微粒体酶诱导的化学物质。建议进行的研究包括 设计用于：(1)确定Oatp1和Oatp1的组成表达水平 Oatp2在成年大鼠肝脏中的表达，并确定其表达是否可诱导 通过微粒体酶诱导剂；(2)确定表达是否增加 微粒体酶诱导成年大鼠燕麦蛋白1和燕麦蛋白2的表达 外源性物质的血浆消失率和肝脏摄取率增加； 确定在仔猪肝脏中是否检测到Oatp1和Oatp2的表达 新生大鼠，以及表达是否在时间上逐渐增加 幼年动物的时尚。我们还将确定是否表达了 幼年动物的燕麦蛋白1和燕麦蛋白2可以被经典的 微粒体酶诱导剂；(4)确定Oatp1和Oatp1的表达是否 新生大鼠和幼年大鼠的OATP2与血浆消失和肝脏 外源生物的摄取；(5)确定转录上调是否 燕麦基因的研究需要最近报道的 孕烷X受体(PXR)-反应元件，提供转录 孕烯醇酮-16α-碳腈(PCN)对多种基因的诱导作用； 确定PCN型诱导剂对OATP的诱导是否涉及PXR。 总体而言，这些研究将确定Oatp1和Oatp2在 肝细胞摄取。

DESCRIPTION (Verbatim from Applicant's Abstract): Cellular uptake of xenobiotics is a fundamental phenomenon required for endogenous biochemicals, pharmaceuticals, and chemicals to elicit any number of biochemical, pharmacological, and/or toxicological events within the cell. It seems intuitive that the mechanism(s) by which xenobiotics are transported into hepatic parenchymal cells will affect the rate at which hepatocellular biotransformation and biliary excretion occur. Transport mechanisms are putatively responsible for the hepatic uptake of organic molecules. The organic anion transporting polypeptides, oatp1 and oatp2, mediate sodium-independent transport of a broad range of organic anions (e.g., bile acids, estrogen conjugates, leukotriene conjugates, unconjugated bilirubin, and cardiac glycosides) into hepatocytes. The oatp1 and oatp2 sinusoidal transporters constitute an important transport system that we postulate to be regulated by both age and microsomal enzyme inducing chemicals. The studies proposed are designed to: (1) determine the constitutive expression levels of oatp1 and oatp2 in liver of adult rats, and determine whether the expression is inducible by microsomal enzyme inducers; (2) determine whether the increased expression of oatp1 and oatp2 in adult rats by microsomal enzyme inducers is related to an increase in plasma disappearance and hepatic uptake of xenobiotics; and (3) determine whether the expression of oatp1 and oatp2 is detectable in liver of newborn rats, and whether the expression progressively increases in a temporal fashion in young animals. We will also determine whether the expression of oatp1 and oatp2 in young animals can be induced to adult levels by classical microsomal enzyme inducers; (4) determine whether the expression of oatp1 and oatp2 in newborn and young rats is related to plasma disappearance and hepatic uptake of xenobiotics; (5) determine whether the transcriptional upregulation of oatp genes requires the involvement of the recently reported pregnane-X-receptor (PXR)-response element that affords transcriptional inducibility of many genes by pregnenolone-16alpha-carbonitrile (PCN); and (6) determine whether the induction of oatps by PCN-type inducers involves the PXR. Overall, these studies will determine the significance of oatp1 and oatp2 in hepatocellular uptake.