REGULATION OF HEPATIC UPTAKE OF DRUGS AND XENOBIOTICS

描述（逐字来自申请人的摘要）： 异生物质是内源性生化物质所需的基本现象， 药物和化学品，以引发任何数量的生化， 药理学和/或毒理学事件。似乎 直觉上，外源性物质被运输到 肝实质细胞将影响肝细胞 发生生物转化和胆汁排泄。传输机制 负责肝脏吸收有机分子的腐殖酸。有机 阴离子转运多肽oatp 1和oatp 2介导钠非依赖性 广泛的有机阴离子（例如，胆汁酸，雌激素 结合物、白三烯结合物、未结合胆红素和心脏 糖苷）进入肝细胞。oatp 1和oatp 2正弦转运蛋白 构成了一个重要的运输系统，我们假设由 年龄和微粒体酶诱导化学物质。拟议的研究包括 设计用于：（1）测定OATP 1的组成型表达水平， oatp 2在成年大鼠肝脏中的表达，并确定其表达是否是可诱导的 通过微粒体酶诱导剂;（2）确定是否增加表达 微粒体酶诱导剂对成年大鼠oatp 1和oatp 2的影响与 异生物质的血浆消失和肝脏摄取增加;和（3） 确定OATP 1和OATP 2的表达是否可在 新生大鼠，以及表达是否逐渐增加，在一个时间 年轻动物的时尚。我们还将确定是否表达 在幼年动物中的oatp 1和oatp 2可以通过经典的 微粒体酶诱导剂;（4）确定OATP 1和 OATP 2在新生和幼年大鼠中与血浆消失和肝 外源性物质的摄取;（5）确定转录上调是否 oatp基因的表达需要最近报道的 孕烷-X-受体（PXR）-反应元件，提供转录 通过双烯醇酮-16 α-腈（PCN）诱导许多基因;和（6） 确定由PCN型诱导剂诱导的oatps是否涉及PXR。 总之，这些研究将确定oatp 1和oatp 2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.