FUNCTION OF XENOBIOTIC RECEPTORS
异生物受体的功能
基本信息
- 批准号:6100854
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
The Ah receptor (AHR) trans-activates the CYP1A1, CYP1A2 and CYP1B1
genes and a number of other target genes after complexing with dioxins
or polycyclic aromatic hydrocarbon. It is beleived to mediate the toxic
and carcinogenic effects of these chemicals. The physiological function
of the AHR is currently unknown, as is the existence of an endogenous
ligand. To determine the role of AHR in development and physiological
homeostasis, and in the biological effect of dioxins, AHR-null mice were
generated. The phenotypes observed in AHR-null mice suggest that the
receptor has an important role in mammalian development and
physiological homeostasis. The liver is clearly not normal with evidence
of fibrosis and altered hepatic architecture. Hepatic contents of
retinoic acid (RA) and its major storage product, retinyl palmitate were
found to be markedly elevated in the AHR-null compared to wild-type
mice. An increase in retinoic acid-responsive genes was also noted. Low
levels of RA metabolism was also found indicating that a cytochrome P450
responsible for RA catabolism is under control of the AHR. Altered RA
levels may cause the fibrosis found in liver and other organs. A
structurally-diverse class of chemicals called peroxisome proliferators
also interact with a family of receptors that are in the steroid
receptor superfamily. Three subunits are found in frogs and mammals,
designated PPAR-alpha, PPAR-beta and PPAR-gamma. The alpha form is most
abundantly expressed in liver and its role regulating enzymes involved
in fatty acid catabolism has been demonstrated. A number of peroxisome
proliferators or potential ligands for PPAR-alpha are also rodent
hepatocarcinogens. This fact is of concern to regulatory agencies, since
humans are exposed to hyperlipidemic drugs, plasticizers used in the
chemical industry, the degreasing agent trichloroethylene and other
chemicals exhibiting peroxisome proliferation activity and
hepatocarcinogenesis potential in rodent model systems. To address the
physiological role of PPAR-alpha and its role in the toxic and
carcinogenic effects of peroxisome proliferators, PPAR-alpha-null mice
were produced. A carcinogenesis bioassay using the potent experimental
peroxisome proliferator Wy-14,643 revealed that PPAR-null mice were
resistant to hepatocarcinogenesis indicating that the receptor mediates
the mechanism of action of the non-genotoxic carcinogen peroxisome
proliferators. PPAR-null mice were also found to be resistant to many,
but not all of the toxicity's found in wild-type mice exposed to the
plasticizer di(2-ethylhehyl)phthalate.
Ah受体(AHR)反式激活CYP 1A 1、CYP 1A 2和CYP 1B 1
基因和其他一些靶基因与二恶英复合后,
或多环芳烃。它被认为是介导毒性的
以及这些化学物质的致癌作用。生理功能
目前尚不清楚AHR的存在,因为存在内源性
配体。确定AHR在发育和生理中的作用
在二恶英的生物学效应中,AHR基因敲除小鼠
生成的.在AHR缺失小鼠中观察到的表型表明,
受体在哺乳动物发育中具有重要作用,
生理稳态肝脏明显不正常
肝纤维化和肝结构改变肝内容物
视黄酸(RA)及其主要贮存产物棕榈酸视黄酯,
发现与野生型相比,在AHR-无效中显著升高
小鼠还注意到视黄酸反应基因的增加。低
也发现RA代谢水平表明细胞色素P450
负责RA catastrophe的是AHR的控制。RA改变
可能导致肝脏和其他器官的纤维化。一
一类结构多样的化学物质,称为过氧化物酶体增殖剂
也与类固醇中的受体家族相互作用
受体超家族青蛙和哺乳动物中发现了三个亚基,
命名为PPAR-alpha、PPAR-beta和PPAR-gamma。阿尔法形式是最
在肝脏中大量表达,并参与调节酶的作用
在脂肪酸催化剂中的作用已得到证实。许多过氧化物酶体
PPAR-alpha的增殖物或潜在配体也是啮齿类动物
肝致癌物。这一事实引起了监管机构的关注,因为
人类暴露于高血脂药物中,
化学工业中的杀菌剂三氯乙烯等
具有过氧化物酶体增殖活性的化学品,
在啮齿动物模型系统中的肝癌发生潜力。解决
PPAR-alpha的生理作用及其在毒性和
过氧化物酶体增殖物的致癌作用,PPAR-alpha-null小鼠
被生产出来。致癌作用生物测定,使用有效的实验
过氧化物酶体增殖剂Wy-14,643显示,
对肝癌发生具有抗性,表明受体介导
非遗传毒性致癌物过氧化物酶体的作用机制
扩散者。还发现无PPAR的小鼠对许多,
但并不是所有的毒性都在野生型小鼠中发现,
增塑剂邻苯二甲酸二(2-乙基)乙酯。
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)
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{{ truncateString('F J GONZALEZ', 18)}}的其他基金
TRANSCRIPTIONAL REGULATION OF GENES ENCODING XENOBIOTIC METABOLIZING ENZYMES
编码异生生物代谢酶的基因的转录调控
- 批准号:
6100823 - 财政年份:
- 资助金额:
-- - 项目类别:
POLYMORPHIC DRUG OXIDATION--THE HUMAN AND RAT DEBRISOQUINE 4-HYDROXYLASE GENES
多态性药物氧化--人和大鼠去溴异喹4-羟化酶基因
- 批准号:
3916876 - 财政年份:
- 资助金额:
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TRANSGENIC MICE, GENE KNOCKOUT MICE, AND CYTOCHROME P450 FUNCTION
转基因小鼠、基因敲除小鼠和细胞色素 P450 功能
- 批准号:
3752741 - 财政年份:
- 资助金额:
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