MOLECULAR DETERMINANTS OF UGT FUNCTION
UGT 功能的分子决定因素
基本信息
- 批准号:6525944
- 负责人:
- 金额:$ 20.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-09-01 至 2005-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (Adapted from Applicant's Abstract): Glucuronidation, catalyzed by
the UDP-glucuronosyltransferase (UGT) enzymes, is an important metabolic
pathway involved in the inactivation and excretion of a multitude of drugs,
toxins, potential carcinogens and endobiotics. The long-term objectives of this
research are to elucidate the molecular determinates of individual variability
in UGT1A6 function. In doing so, it may then be possible to identify
individuals within a population that may be at high risk for adverse drug
reactions and interactions, susceptibility to environmental toxins and
carcinogens, as well as those with inborn errors of endogenous metabolism.
UGT1A6 preferentially glucuronidates planar phenolic xenobiotics and
substantially contributes to the biotransformation of acetaminophen.
Acetaminophen glucuronidation in humans appears to be heterogenous and the
molecular basis for this phenomenon is currently unknown. There is evidence for
functionally relevant polymorphisms in the human UGT1A6 gene, which may affect
either substrate affinity or enzyme content. Furthermore, recent studies
suggest that UGT isoforms can form heterodimers which could modulate
UTG1A6-mediated glucuronidation through protein-protein interactions. Three
specific aims are proposed: (1) To utilize acetaminophen as a probe substrate
for UTG1A6-mediated glucuronidation which will be substantiated by comparative
activity and enzyme kinetic determinations using currently available
cDNA-expressed UGT isoforms, and by isoform-specific immunoinhibition of
acetaminophen glucuronidation in human liver microsomes: (2) To investigate the
influence of polymorphisms in the UGT1A6 gene on isoenzyme content and specific
activity ascertained by comparisons of expressed wild-type and variant UGT1A6,
and by phenotypic-genotypic analyses using human liver microsomes and (3) To
investigate the potential role for protein-protein interactions in modulating
UGT1A6-mediated glucuronidation by identifying interacting proteins with the
yeast two-hybrid expression system, and substantiating the functional
significance of these interactions by coexpression studies.
描述(改编自申请人摘要):葡萄糖醛酸化,由
UDP-葡萄糖醛酸基转移酶(UGT)是一种重要的代谢酶,
参与多种药物的失活和排泄的途径,
毒素、潜在致癌物和内毒素。这一长期目标
研究的目的是阐明个体差异的分子决定因素
UGT1A6功能。这样,就有可能确定
人群中可能存在不良药物高风险的个体
反应和相互作用,对环境毒素的敏感性,
致癌物,以及那些与先天性缺陷的内源性代谢。
UGT1A6优先葡糖醛酸化平面酚类异生物质,
基本上有助于对乙酰氨基酚的生物转化。
人体中对乙酰氨基酚葡萄糖醛酸化似乎是异质性的,
这种现象的分子基础目前尚不清楚。有证据表明
人类UGT1A6基因的功能相关多态性,可能影响
底物亲和力或酶含量。此外,最近的研究
表明UGT同工型可以形成异二聚体,从而可以调节
UTG1A6通过蛋白质-蛋白质相互作用介导的葡萄糖醛酸化。三
具体目标是:(1)利用对乙酰氨基酚作为探针底物
对于UTG1A6介导的葡萄糖醛酸化,将通过比较
活性和酶动力学测定,
cDNA表达的UGT亚型,并通过亚型特异性免疫抑制
对乙酰氨基酚在人肝微粒体中的葡萄糖醛酸化:(2)研究
UGT 1A6基因多态性对同工酶含量和特异性的影响
通过比较表达的野生型和变体UGT 1A6确定活性,
以及通过使用人肝微粒体的表型-基因型分析和(3)
研究蛋白质-蛋白质相互作用在调节
UGT 1A6介导的葡萄糖醛酸化,通过鉴定与
酵母双杂交表达系统,并证实了功能
通过共表达研究这些相互作用的意义。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Michael H Court其他文献
Assessment of cytochrome P450 induction in canine intestinal organoid models
犬肠道类器官模型中细胞色素 P450 诱导的评估
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Itsuma Nagao;Meg Nakazawa;Takashi Goyama;Michael H Court;Yoko M. Ambrosini - 通讯作者:
Yoko M. Ambrosini
Abstracts presented at the World Congress of Veterinary Anaesthesiology, September 12–16, 2006, Santos, Brazil
- DOI:
10.1111/j.1467-2995.2007.00371a.x - 发表时间:
2007-07-01 - 期刊:
- 影响因子:
- 作者:
B Duncan X Lascelles;Michael H Court;Elizabeth M Hardie;Sheilah A Robertson - 通讯作者:
Sheilah A Robertson
Michael H Court的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Michael H Court', 18)}}的其他基金
MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
- 批准号:
8514016 - 财政年份:2012
- 资助金额:
$ 20.88万 - 项目类别:
MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
- 批准号:
8574401 - 财政年份:2012
- 资助金额:
$ 20.88万 - 项目类别:
MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
- 批准号:
8341339 - 财政年份:2012
- 资助金额:
$ 20.88万 - 项目类别:
MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
- 批准号:
8827811 - 财政年份:2012
- 资助金额:
$ 20.88万 - 项目类别:
MicroRNAs as effectors of variable human drug metabolism
MicroRNA 作为可变人类药物代谢的效应器
- 批准号:
8653584 - 财政年份:2012
- 资助金额:
$ 20.88万 - 项目类别:
Mechanisms of adverse host responses to antibiotics
宿主对抗生素不良反应的机制
- 批准号:
7054675 - 财政年份:2005
- 资助金额:
$ 20.88万 - 项目类别:
Mechanisms of adverse host responses to antibiotics
宿主对抗生素不良反应的机制
- 批准号:
6925811 - 财政年份:2005
- 资助金额:
$ 20.88万 - 项目类别:
相似海外基金
Molecular mechanisms of animal tissue morphogenesis
动物组织形态发生的分子机制
- 批准号:
572569-2022 - 财政年份:2022
- 资助金额:
$ 20.88万 - 项目类别:
University Undergraduate Student Research Awards
Feasibility of an integrated ultrasonic enhanced extraction and magneto-immunoassay technique for rapid, in-situ measurement of antibiotic residues in animal tissue
集成超声增强提取和磁免疫分析技术快速原位测量动物组织中抗生素残留的可行性
- 批准号:
131482 - 财政年份:2014
- 资助金额:
$ 20.88万 - 项目类别:
Feasibility Studies
Development of novel fluorescent dye for multiphoton imaging of deep region of animal tissue
开发用于动物组织深部多光子成像的新型荧光染料
- 批准号:
25560411 - 财政年份:2013
- 资助金额:
$ 20.88万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Cell signaling fine-tuning that supports animal tissue development and homeostasis
支持动物组织发育和稳态的细胞信号微调
- 批准号:
25293072 - 财政年份:2013
- 资助金额:
$ 20.88万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Validation of LC-MS/MS analyses of animal tissue and feed matrices for toxicants
验证动物组织和饲料基质中有毒物质的 LC-MS/MS 分析
- 批准号:
9326829 - 财政年份:2013
- 资助金额:
$ 20.88万 - 项目类别:
Rapid, in-situ measurement of antibiotic residues in animal tissue
快速原位测量动物组织中的抗生素残留
- 批准号:
750767 - 财政年份:2013
- 资助金额:
$ 20.88万 - 项目类别:
Vouchers
Validation of LC-MS/MS analyses of animal tissue and feed matrices for toxicants
验证动物组织和饲料基质中有毒物质的 LC-MS/MS 分析
- 批准号:
8701722 - 财政年份:2013
- 资助金额:
$ 20.88万 - 项目类别:
Validation of LC-MS/MS analyses of animal tissue and feed matrices for toxicants
验证动物组织和饲料基质中有毒物质的 LC-MS/MS 分析
- 批准号:
8908915 - 财政年份:2013
- 资助金额:
$ 20.88万 - 项目类别:
Cellular and molecular mechanisms shaping animal tissue architecture
塑造动物组织结构的细胞和分子机制
- 批准号:
183749-2009 - 财政年份:2013
- 资助金额:
$ 20.88万 - 项目类别:
Discovery Grants Program - Individual
Cellular and molecular mechanisms shaping animal tissue architecture
塑造动物组织结构的细胞和分子机制
- 批准号:
183749-2009 - 财政年份:2012
- 资助金额:
$ 20.88万 - 项目类别:
Discovery Grants Program - Individual