RIFAMPIN ON HEPATIC CYP3A ACTIVITY IN HEALTHY VOLUNTEERS

利福平对健康志愿者肝 CYP3A 活性的影响

基本信息

  • 批准号:
    6304222
  • 负责人:
  • 金额:
    $ 3.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1999
  • 资助国家:
    美国
  • 起止时间:
    1999-12-01 至 2000-11-30
  • 项目状态:
    已结题

项目摘要

The liver plays an important role in the interaction between man and his chemical environment. A major locus of this interaction in human beings is the liver microsomal hemoprotein cytochrome P450 (CYP3A4). CYP3A4 catalyzes and in many instances may limit the metabolism of over 70% of the clinically used drugs as well as numerous environmental pollutants, carcinogens, and such endogenous substrates as steroid hormones. The CYP3A enzyme in human liver, originally was identified from the pioneering efforts of the celebrated biologist, Hans Selye who identified an inducible activity in rat liver that appeared to play a protective role in animals placed under conditions of chronic stress through physiologic or pharmacologic means. Indeed, there has never been a human identified who lacks CYP3A activity, a finding that suggests that this enzyme plays some essential role in liver metabolism. Measurements of the amounts of CYP3A from human liver biopsies as well as from non-invasive techniques indicate a wide variation among patients, about ten-fold. The amounts of CYP3A in human liver are indeed inducible by such clinically relevant drugs as dexamethasone and the antibiotic rifampin. However, there is no information available on the frequency or magnitude of induction of CYP3A among populations of normal humans. Older literature contains inferences that some people may lack the ability to respond to rifampin with an increase in CYP3A activity. Our hypothesis is that lack of inducibility of CYP3A in the liver may contribute to stress-related diseases due to a failure to metabolically eliminate glucocorticoids and other endogenous products generated under conditions of chronic stress. Rapidly developing information of genetic polymorphisms for families of genes whose products are intimately involved in the activation or inactivation of toxic chemicals emphasize the importance of developing information on interindividual differences in susceptibility. Although the CYP3A enzymes exhibit a wide range of interindividual variability in their levels in liver, no genetic component reponsible for polymorphism in their expression has been confirmed. Critically needed for evaluation of the clinical importance of putative regulatory regions of this gene is phenotypic identification of humans who are either over or under expressers with regards to its drug mediated inducibility. In this study we propose to: 1) use a non-invasive measure of liver CYP3A activity, specifically the erythromycin breath test, to determine the amounts of CYP3A in the basal steady state and after induction by orally administered rifampin in normal human volunteers, 2) provide a confirmation of CYP3A induction in these volunteers by measuring changes in rifampin half-life before and after one week of treatment with rifampin, and 3) analyze DNA isolated from individuals phenotyped for CYP3A4 activity in order to associate a specific CYP3A4 genotype with a specific CYP3A4 phenotype.
肝脏在人与化学环境的相互作用中起着重要的作用。在人类中,这种相互作用的一个主要位点是肝微粒体血色素P450(CYP3A4)。CYP3A4催化并在许多情况下可能限制超过70%的临床用药以及大量环境污染物、致癌物和类固醇激素等内源性底物的代谢。人类肝脏中的CYP3A酶最初是从著名生物学家汉斯·塞尔耶的开创性努力中发现的,他在大鼠肝脏中发现了一种可诱导的活动,似乎通过生理或药物手段在处于慢性应激条件下的动物中发挥保护作用。事实上,从来没有人被发现缺乏CYP3A活性,这一发现表明这种酶在肝脏新陈代谢中扮演着一些重要的角色。对人类肝脏活检和非侵入性技术中的CYP3A含量的测量表明,患者之间存在很大的差异,大约是患者的十倍。人体肝脏中的细胞色素P3A确实可以被地塞米松和抗生素利福平等临床相关药物诱导。然而,目前还没有关于在正常人群中诱导CYP3A的频率或大小的信息。较早的文献推断,一些人可能缺乏通过增加细胞色素P3A活性来应对利福平的能力。我们的假设是,肝脏中缺乏CYP3A的诱导性可能是由于未能代谢消除慢性应激条件下产生的糖皮质激素和其他内源性产物而导致应激相关疾病。其产物与有毒化学物质的激活或灭活密切相关的基因家族的遗传多态信息迅速发展,强调了开发关于个体间易感性差异的信息的重要性。尽管CYP3A酶在肝脏中的水平显示出广泛的个体间差异,但尚未证实与其表达的多态有关的遗传成分。对于评估该基因的假定调控区的临床重要性来说,关键需要的是对药物介导的诱导性过高或过低的人类进行表型鉴定。在这项研究中,我们建议:1)使用一种非侵入性的肝细胞色素P3A活性测量方法,特别是红霉素呼气试验,来确定正常志愿者在基础稳态和口服利福平诱导后的细胞色素P3A的量;2)通过测量利福平治疗一周前和一周后利福平半衰期的变化来证实这些志愿者中细胞色素P3A的诱导;以及3)分析从细胞色素P3A4活性表型的个体中分离出来的DNA,以便将特定的CYP3A4基因与特定的细胞色素P3A4表型联系起来。

项目成果

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PHILIP S GUZELIAN其他文献

PHILIP S GUZELIAN的其他文献

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{{ truncateString('PHILIP S GUZELIAN', 18)}}的其他基金

EVAL OF THE EFFECT OF RIFAMPIN ON HEPATIC CYP3A ACTIVITY IN HEALTHY VOLUNTEERS
利福平对健康志愿者肝 CYP3A 活性影响的评估
  • 批准号:
    7200517
  • 财政年份:
    2005
  • 资助金额:
    $ 3.22万
  • 项目类别:
RIFAMPIN ON HEPATIC CYP3A ACTIVITY IN HEALTHY VOLUNTEERS
利福平对健康志愿者肝 CYP3A 活性的影响
  • 批准号:
    6504443
  • 财政年份:
    2000
  • 资助金额:
    $ 3.22万
  • 项目类别:
RIFAMPIN ON HEPATIC CYP3A ACTIVITY IN HEALTHY VOLUNTEERS
利福平对健康志愿者肝 CYP3A 活性的影响
  • 批准号:
    6566295
  • 财政年份:
    2000
  • 资助金额:
    $ 3.22万
  • 项目类别:
RIFAMPIN ON HEPATIC CYP3A ACTIVITY IN HEALTHY VOLUNTEERS
利福平对健康志愿者肝 CYP3A 活性的影响
  • 批准号:
    6263995
  • 财政年份:
    1998
  • 资助金额:
    $ 3.22万
  • 项目类别:
CORE--HUMAN HEPATOCYTE CULTURE AND TISSUE BANK
核心--人肝细胞培养和组织库
  • 批准号:
    6106135
  • 财政年份:
    1996
  • 资助金额:
    $ 3.22万
  • 项目类别:
STRUCTURE AND EXPRESSION OF CLASS III CYTOCHROME P-450 GENES IN MAN
人类 III 类细胞色素 P-450 基因的结构和表达
  • 批准号:
    6106132
  • 财政年份:
    1996
  • 资助金额:
    $ 3.22万
  • 项目类别:
STRUCTURE, FUNCTION AND REGULATION OF CYTOCHROME P450
细胞色素 P450 的结构、功能和调控
  • 批准号:
    2145399
  • 财政年份:
    1992
  • 资助金额:
    $ 3.22万
  • 项目类别:
INTEGRATED CLINICAL & BASIC STUDIES OF TOXICOLOGY
综合临床
  • 批准号:
    2153615
  • 财政年份:
    1987
  • 资助金额:
    $ 3.22万
  • 项目类别:
INTEGRATED CLINICAL & BASIC STUDIES OF HUMAN TOXICOLOGY
综合临床
  • 批准号:
    3095935
  • 财政年份:
    1987
  • 资助金额:
    $ 3.22万
  • 项目类别:
INTEGRATED CLINICAL & BASIC STUDIES OF TOXICOLOGY
综合临床
  • 批准号:
    2153616
  • 财政年份:
    1987
  • 资助金额:
    $ 3.22万
  • 项目类别:

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