REGULATION OF HEPATIC P450S BY ANTICHOLESTEROL DRUGS

抗胆固醇药物对肝脏 P450S 的调节

基本信息

  • 批准号:
    6183394
  • 负责人:
  • 金额:
    $ 22.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1993
  • 资助国家:
    美国
  • 起止时间:
    1993-08-01 至 2004-03-31
  • 项目状态:
    已结题

项目摘要

Emerging evidence suggests that the complex processes of sterol biosynthesis and xenobiotic metabolism by enzymes of the cytochrome P450 superfamily are inextricably intertwined. Such an interrelationship has important implications for the safety and efficacy of the growing arsenal of "anti-cholesterol" drugs that is being developed to lower patients' plasma cholesterol levels and thereby treat or prevent coronary artery disease. The hypothesis of this proposal is three-fold: (1) Anti-cholesterol drugs that inhibit sterol biosynthesis, such as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase or squalene synthase, induce rat hepatic CYP2B1 gene expression by causing depletion of the critical cellular sterols that suppress CYP2B1 expression in the basal steady state, which results in activation of sterol regulatory element binding proteins (SREBP), followed by transcriptional activation of the CYP2B1 gene through specific 5'- flanking sequences contained within the phenobarbital responsive unit. (2) Anti-cholesterol drugs, such as inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) or squalene cyclase, that promote accumulation of specific cellular sterols, such as 24(S),25-epoxycholesterol, induce CYP3A23 gene expression through a mechanism whereby the accumulated sterols activate the LXRalpha nuclear receptor, resulting in transcriptional activation of the CYP3A23 gene through a specific sterol-responsive 5'-flanking sequence. (3) HMG-CoA reductase inhibitors induce CYP4A gene expression through a mechanism that requires increased fatty acid biosynthesis, activation of the peroxisome proliferation associated receptor alpha (PPARalpha) and transcriptional activation of the CYP4A1 gene through a peroxisome proliferator responsive element. The specific aims of this proposal are to (1) define the effects of chemical inhibitors of key steps of the cholesterol biosynthesis and esterification pathways on P450 expression in primary cultured rat hepatocytes, and to relate patterns of gene expression to changes in levels of specific cellular sterols, (2) identify the 5'-flanking sequence(s) that confer HMG-CoA reductase inhibitor-and squalene synthase inhibitor-inducible transcriptional activation to the CYP2B1 gene, and to determine whether this regulation is mediated through an SREBP transcription factor, (3) identify the 5'- flanking sequence(s) that confer sterol-, ACAT inhibitor-and squalene cyclase inhibitor-inducible transcriptional activation to the CYP3A23 gene, and to determine whether this regulation is mediated through the LXRalpha nuclear receptor and (4) determine whether HMG-CoA reductase inhibitor-inducible CYP4A1 induction occurs through a mechanism that requires elevated fatty acid biosynthesis and activation of PPARalpha. These studies will provide information with practical implications for the development of improved anti-cholesterol drugs, and will illuminate mechanisms whereby a cell recognizes, responds to, and metabolizes foreign chemicals.
新出现的证据表明, 细胞色素P450酶的生物合成和异生物质代谢 超家族是不可分割地交织在一起的。 这种相互关系 重要的影响,安全性和有效性的日益增长的 正在开发的“抗胆固醇”药物库, 患者的血浆胆固醇水平,从而治疗或预防 冠状动脉疾病 这一建议的假设有三个方面: (1)抑制固醇生物合成的抗胆固醇药物,如 3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶的抑制剂 或角鲨烯合酶,诱导大鼠肝脏CYP 2B 1基因表达, 导致抑制CYP 2B 1的关键细胞固醇耗尽 表达在基础稳态,这导致激活 固醇调节元件结合蛋白(SREBP),然后 CYP 2B 1基因的转录激活,通过特异性5 '- 包含在苯巴比妥反应单元内的侧翼序列。 (2)抗胆固醇药物,如酰基辅酶A:胆固醇抑制剂 酰基转移酶(ACAT)或角鲨烯环化酶,促进积累 特定的细胞甾醇,如24(S),25-环氧胆固醇,诱导 CYP 3A 23基因表达通过一种机制, 固醇激活LXR α核受体,导致 CYP 3A 23基因的转录激活通过一个特异性的 甾醇响应性5 '侧翼序列。 (3)HMG-CoA还原酶 抑制剂通过一种机制诱导CYP 4A基因表达, 需要增加脂肪酸的生物合成,激活过氧化物酶体 增殖相关受体α(PPARalpha)和转录 通过过氧化物酶体增殖剂激活CYP 4A 1基因 响应元件 本建议的具体目标是:(1) 确定化学抑制剂的关键步骤的影响, 胆固醇合成和酯化途径对P450表达的影响 在原代培养大鼠肝细胞中, 表达与特定细胞固醇水平的变化,(2) 鉴定赋予HMG-CoA还原酶的5 '侧翼序列 角鲨烯和角鲨烯合酶基因可诱导的转录 激活CYP 2B 1基因,并确定这种调节是否 通过SREBP转录因子介导,(3)鉴定5 '- 赋予甾醇、ACAT甾醇和角鲨烯的侧翼序列 CYP 3A 23的环化酶底物可诱导的转录激活 基因,并确定这种调节是否是通过介导的 LXR α核受体和(4)确定HMG-CoA还原酶是否 通过一种机制, 需要升高的脂肪酸生物合成和激活PPARalpha。 这些研究将提供具有实际意义的信息, 开发改进的抗胆固醇药物,并将阐明 细胞识别、响应和代谢的机制 外国化学品

项目成果

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Thomas A Kocarek其他文献

Thomas A Kocarek的其他文献

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{{ truncateString('Thomas A Kocarek', 18)}}的其他基金

Pilot Project Program
试点项目计划
  • 批准号:
    8619370
  • 财政年份:
    2014
  • 资助金额:
    $ 22.72万
  • 项目类别:
CORE--Cell Culture Facilities Core
CORE--细胞培养设施核心
  • 批准号:
    6750897
  • 财政年份:
    2004
  • 资助金额:
    $ 22.72万
  • 项目类别:
CORE-- CELL CULTURE
核心--细胞培养
  • 批准号:
    6597607
  • 财政年份:
    2002
  • 资助金额:
    $ 22.72万
  • 项目类别:
CORE-- CELL CULTURE
核心--细胞培养
  • 批准号:
    6446935
  • 财政年份:
    2001
  • 资助金额:
    $ 22.72万
  • 项目类别:
CORE-- CELL CULTURE
核心--细胞培养
  • 批准号:
    6301455
  • 财政年份:
    2000
  • 资助金额:
    $ 22.72万
  • 项目类别:
CORE-- CELL CULTURE
核心--细胞培养
  • 批准号:
    6347450
  • 财政年份:
    2000
  • 资助金额:
    $ 22.72万
  • 项目类别:
CORE-- CELL CULTURE
核心--细胞培养
  • 批准号:
    6106375
  • 财政年份:
    1999
  • 资助金额:
    $ 22.72万
  • 项目类别:
CORE-- CELL CULTURE
核心--细胞培养
  • 批准号:
    6271242
  • 财政年份:
    1998
  • 资助金额:
    $ 22.72万
  • 项目类别:
CORE-- CELL CULTURE
核心--细胞培养
  • 批准号:
    6239661
  • 财政年份:
    1997
  • 资助金额:
    $ 22.72万
  • 项目类别:
REGULATION OF HEPATIC P450S BY ANTICHOLESTEROL DRUGS
抗胆固醇药物对肝脏 P450S 的调节
  • 批准号:
    6389301
  • 财政年份:
    1993
  • 资助金额:
    $ 22.72万
  • 项目类别:

相似海外基金

Scaffolds for Synthesis of Probes Directed Against Class II HMG-CoA Reductases
用于合成针对 II 类 HMG-CoA 还原酶的探针的支架
  • 批准号:
    7367432
  • 财政年份:
    2007
  • 资助金额:
    $ 22.72万
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