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
- 来源:
- 关键词:DNA footprinting HMG coA reductases antihypercholesterolemic agent cytochrome P450 enzyme activity enzyme induction /repression enzyme inhibitors esterase inhibitor fatty acid synthase gel mobility shift assay gene expression genetically modified animals laboratory mouse laboratory rat lipid metabolism liver cells liver metabolism oxidoreductase inhibitor squalene sterols tissue /cell culture transcription factor transfection
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
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)
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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
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:
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