HEPATIC DRUG TRANSPORTERS IN DRUG DISPOSITION
HEPATIC DRUG TRANSPORTERS IN DRUG DISPOSITION
批准号:
6019193
负责人:
RICHARD B KIM
金额:
$10.65万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-07-01 至 2003-06-30
中文摘要
本应用程序的总体目标是加深我们对
载体介导的过程在摄取
外源物质从体循环进入肝脏--这是至关重要的第一步
让他们的肝脏排出。一些人的肝脏
基底膜转运蛋白最近被克隆和
具有关于内源的运输的功能特征
胆汁酸等化合物。我们克隆了两个新的人类
与大鼠有机器官序列同源的肝药物转运蛋白
阳离子转运蛋白(ROCT1)和人有机阴离子转运蛋白
(HOATP)。此外,我们还发现了一种突变(Phe83-
>;Ser83)在人肝脏钠依赖胆汁酸转运体中,
HNTCP,由单个T->C替换产生,它具有标记的
减少其运输活动。我们的假设是这些
运输系统识别临床上使用的各种药物,并且
功能或活动的可变性在以下方面具有重要意义
戒毒和治疗。因此,建议进行研究以检验
通过个体功能表达的特定假说
传送者。在特定目标1中拟议的研究将测试
假设我们新克隆的转运蛋白hOATP2和hNLT,
代表具有生物化学特征的多特异性胆汁酸
转运蛋白和肝脏特异性有机阳离子转运蛋白。
我们还将定义突变体hNTCP的转运动力学
以评估该突变是否改变底物亲和力。
此外,这一假设将得到检验,即通过hNTCP传输
在牛磺熊去氧胆酸的治疗反应中起关键作用
酸(在淤胆性肝病中)和奥曲肽(在癌症中)
化疗)。特定目标2专注于定点突变
和同源嵌合体构建方法,将用于
更好地了解和确定与传输者相关的关键领域
活性和底物专一性。这些研究将提供重要的
关于人体肝脏药物转运系统的见解,并增强
我们对这种过程在药物处置中的作用的理解。
英文摘要
The overall objective of this application is to further our understanding
of the role of carrier-mediated processes responsible for the uptake of
xenobiotics from the systemic circulation into the liver -a critical first
step in their hepatic elimination. A number of human hepatic
basolateral membrane transporters have recently been cloned and
functionally characterized with respect to the transport of endogenous
compounds such as bile acids. We have cloned two novel human
hepatic drug transporters with sequence homologies to the rat organic
cation transporter (rOCT1), and the human organic anion transporter
(hOATP). In addition, we have identified a mutation (Phe83-
>Ser83)in the human hepatic sodium-dependent bile acid transporter,
hNTCP, resulting from a single T->C substitution, that has a marked
reduction in its transport activity. It is our hypothesis that these
transport systems recognize a variety of drugs in clinical use, and that
variability in function or activity has important implications in terms of
drug elimination and therapy. Therefore, studies are proposed to test
specific hypothesis through functional expression of individual
transporters. The proposed studies in Specific Aim 1 will test the
hypothesis that our newly cloned transporters, hOATP2 and hNLT,
represent the biochemically characterized multispecific bile acid
transporter, and a liver specific organic cation transporter, respectively.
We will also define the transport kinetics of the mutant hNTCP
transporter to assess whether this mutation alters substrate affinity.
Additionally, the hypothesis will be tested that transport by hNTCP
plays a pivotal role in the therapeutic response to tauroursodeoxycholic
acid (in cholestatic liver disease) and to octreotide (in cancer
chemotherapy). Specific Aim 2 focusses on site-directed mutagenesis
and homologous chimera construction methods that will be used to
better understand and identify key domains conferring transporter
activity and substrate specificity. These studies will provide important
insights regarding human hepatic drug transport systems, and enhance
our understanding of the role of such processes in drug disposition.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
INTESTINAL AND HEPATIC DRUG TRANSPORTERS
-
批准号:6482470
-
项目类别:
-
资助金额:$14.08万
-
财政年份:2001
-
负责人:RICHARD B KIM
-
依托单位:
INTESTINAL AND HEPATIC DRUG TRANSPORTERS
-
批准号:6325865
-
项目类别:
-
资助金额:$26.76万
-
财政年份:2000
-
负责人:RICHARD B KIM
-
依托单位:
INTESTINAL AND HEPATIC DRUG TRANSPORTERS
-
批准号:6107501
-
项目类别:
-
资助金额:$26.76万
-
财政年份:1999
-
负责人:RICHARD B KIM
-
依托单位:
HEPATIC DRUG TRANSPORTERS IN DRUG DISPOSITION
-
批准号:2378344
-
项目类别:
-
资助金额:$16.25万
-
财政年份:1998
-
负责人:RICHARD B KIM
-
依托单位:
Hepatic Drug Transporters in Drug Disposition
-
批准号:6909064
-
项目类别:
-
资助金额:$44.9万
-
财政年份:1998
-
负责人:RICHARD B KIM
-
依托单位:
HEPATIC DRUG TRANSPORTERS IN DRUG DISPOSITION
-
批准号:6180909
-
项目类别:
-
资助金额:$16.91万
-
财政年份:1998
-
负责人:RICHARD B KIM
-
依托单位:
HEPATIC DRUG TRANSPORTERS IN DRUG DISPOSITION
-
批准号:6386552
-
项目类别:
-
资助金额:$17.41万
-
财政年份:1998
-
负责人:RICHARD B KIM
-
依托单位:
HEPATIC DRUG TRANSPORTERS IN DRUG DISPOSITION
-
批准号:6519770
-
项目类别:
-
资助金额:$17.93万
-
财政年份:1998
-
负责人:RICHARD B KIM
-
依托单位:
INTESTINAL AND HEPATIC DRUG TRANSPORTERS
-
批准号:6271743
-
项目类别:
-
资助金额:$26.11万
-
财政年份:1998
-
负责人:RICHARD B KIM
-
依托单位:
Hepatic Drug Transporters in Drug Disposition
-
批准号:6685485
-
项目类别:
-
资助金额:$38.52万
-
财政年份:1998
-
负责人:RICHARD B KIM
-
依托单位:
Hepatic Drug Transporters in Drug Disposition
-
批准号:6766010
-
项目类别:
-
资助金额:$39.67万
-
财政年份:1998
-
负责人:RICHARD B KIM
-
依托单位:
INTESTINAL AND HEPATIC DRUG TRANSPORTERS
-
批准号:6240424
-
项目类别:
-
资助金额:$28.41万
-
财政年份:1997
-
负责人:RICHARD B KIM
-
依托单位:
HEPATIC DRUG TRANSPORTERS IN DRUG DISPOSITION
-
批准号:2659252
-
项目类别:
-
资助金额:$10.0万
-
财政年份:1997
-
负责人:RICHARD B KIM
-
依托单位:
海外基金