Molecular Mechanisms of Toxic Expression Induced by Endocrine Disruptors via AHR

内分泌干​​扰物通过 AHR 诱导毒性表达的分子机制

• 批准号: 15390040
• 负责人: YAMAZAKI Hiroshi
• 金额: $ 8.64万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390040/
• 关键词: AHR; PAHs; TCDD; CYP1A1; CYP1B1; 個人差

Polycychc aromatic hydrocarbons (PAHs) which are known as the Environmental Endocrine Disruptors exert the various toxicological effects via aryl hydrocarbon receptor (AHR). However the mechanisms of toxic expression induced by PAHs have not been clarified yet. Therefore, the purpose of this study was to clarify the mechanisms of toxic expression induced by PAHs using differential display method and DNA microarray method. First, total RNA were prepared from the wild type mouse and AHR knock out mouse livers treated. with 3-methylcholanthrene (MC). We found the novel AHR target genes using differential display method and DNA microarray method. Interestingly, the mRNA expressions of the peroxisome prolifilator-activated receptor (PPAR) α target genes were suppressed by PAH treatment through AHR. We also demonstrated that AHR inhibited PPARα signals through the suppression of its heterodimeric partner, retinoid X receptor (RXR)α. The genes responsible for the fatty acid metabolism were regulated by PPARα. Therefore, it was suggested that the suppression of the PPARα signal was important for the occurrence of fatty liver.

多环芳烃（PAHs）被称为环境内分泌干扰物，通过芳基烃受体（AHR）发挥多种毒理学作用，但PAHs诱导毒性表达的机制尚未阐明，因此本研究的目的是。为了阐明PAHs诱导的毒性表达机制，首先，从野生型小鼠和经AHR处理的小鼠肝脏中制备总RNA。 3-甲基胆蒽（MC）。我们使用差异显示方法和DNA微阵列方法发现了新的AHR靶基因，通过AHR治疗，过氧化物酶体增殖物激活受体（PPAR）α靶基因的mRNA表达受到抑制。还证明 AHR 通过抑制其异二聚体伴侣视黄醇 X 受体 (RXR)α 来抑制 PPARα 信号。负责脂肪酸代谢的基因受 PPARα 调节。因此提示PPARα信号的抑制对于脂肪肝的发生具有重要意义。

项目成果

Toide K, Yamazaki H, et al.: "Aryl hydrocarbon hydroxylase represents CYP1B1, and not CYP1A1, in human freshly isolated white cells"Cancer Epidem Biomarker Prev. 12. 219-222 (2003)

Toide K、Yamazaki H 等人：“在人类新鲜分离的白细胞中，芳基烃羟化酶代表 CYP1B1，而不是 CYP1A1”Cancer Epidem Biomarker Prev.

Identification of a novel polymorphic enhancer of the human CYP3A4 gene

• DOI: 10.1124/mol.65.2.326
• 发表时间: 2004-02-01
• 期刊: MOLECULAR PHARMACOLOGY
• 影响因子: 3.6
• 作者: Matsumura, K;Saito, T;Kamataki, T
• 通讯作者: Kamataki, T

Toide K, Yamazaki H, Kamataki T: "Reply : Correspondence re : K.Toide et al."Cancer Epidem Biomarker Prev. 12. 1118 (2003)

Toide K、Yamazaki H、Kamataki T：“回复：通讯：K.Toide 等人”Cancer Epidem Biomarker Prev。

CYP3A5 Contributes significantly to CYP3A-mediated drug oxidations in liver microsomes from Japanese subjects.

• DOI: 10.2133/dmpk.19.120
• 发表时间: 2004-04-01
• 期刊: Drug metabolism and pharmacokinetics
• 影响因子: 2.1
• 作者: Yamaori, Satoshi;Yamazaki, Hiroshi;Kamataki, Tetsuya
• 通讯作者: Kamataki, Tetsuya

Yamaori S, Yamazaki H, et al.: "Effects of cytochrome b5 on drug oxidation activities of human cytochrome P450 (CYP) 3As"Biochem Pharmacol. 66. 2333-2340 (2003)

Yamaori S、Yamazaki H 等人：“细胞色素 b5 对人细胞色素 P450 (CYP) 3As 药物氧化活性的影响”Biochem Pharmacol。