Organ specific regulation of sterol 14-demethylase P450 expression relating to its organ specific functions

甾醇14-去甲基化酶P450表达的器官特异性调节与其器官特异性功能相关

• 批准号: 13672316
• 负责人: YOSHIDA Yuzo
• 金额: $ 2.24万
• 依托单位: Mukogawa Women's University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672316/
• 关键词: CYP51; Cytochrome P450; Sterol biosynthesis; Oocyte maturation; Meiosis activating sterol; Insulin; SREBP; Regulatory mechanism of expression; ステロール合成酵素; ホルモン; 脳; Caco-2細胞; 転写調節エレメント; 小腸; 副腎; 肝臓; 卵巣

This subject consists of a part of our research project for examining organ specific regulatory mechanisms of sterol 14-demethylase P450(CYP51) expression relating to its organ specific functions. CYP51 is a unique P450 that expresses ubiquitously in mammalian organs. However, its expression level was considerably different among organs, suggesting that expression of CYP51 might be regulated differently by organ specific manners. Then, effects of several hormones on the CYP51 expression levels in liver, small intestine, adrenal gland, brain and ovary of rats were examined. The most interesting finding was specific induction of ovarian CYP51 by a gonadotropin(PMSG). Since 14-demethylated derivatives of lanosterol have been identified as mammalian meiosis activating sterols(MAS), the gonadotropin dependent expression of ovarian CYP51 might be related to this ovary specific function of CYP51. The immunohistochemical observation indicating that the gonadotropin-dependent expression of CYP5 … More 1 was localized at tumulus and granulosa cells close to oocyte supported this possibility. The expression of hepatic CYP51 was dependent on insulin. The enhancing effect of insulin was explained by its inducing effect on SREBP-1c, as in the case of other lipid metabolizing enzymes. This fact indicated that the expression of hepatic CYP51 might be regulated as a member of lipid-metabolizing enzymes. It was also shown that expression of CYP51 in liver, small intestine and adrenal gland was dependent on thyroid hormone. The thyroid hormone-dependent expression of CYP51 was repressed by dexamethazone(dex), and dex reduced the CYP51 contents in liver, small intestine and adrenal gland. Dose response experiments suggested the contribution of glucocorticoid receptor to the repressive effect of dex on CYP51 expression. No substantial difference was observed between the hormonal regulation of CYP51 expression in brain and liver. Essential role of SER,CRE and a GCAAT element on CYP51 expression was also suggested. Less

本课题是我们研究甾醇14-去甲基化酶P450（CYP 51）表达的器官特异性调控机制的一部分。CYP 51是一种独特的P450，在哺乳动物器官中广泛表达。然而，其表达水平在器官之间存在很大差异，这表明CYP 51的表达可能受到器官特异性方式的不同调节。然后，研究了几种激素对大鼠肝脏、小肠、肾上腺、脑和卵巢中CYP 51表达水平的影响。最有趣的发现是促性腺激素（PMSG）对卵巢CYP 51的特异性诱导。由于羊毛甾醇的14-去甲基化衍生物已被鉴定为哺乳动物减数分裂激活甾醇（MAS），卵巢CYP 51的促性腺激素依赖性表达可能与CYP 51的卵巢特异性功能有关。免疫组化观察表明，促性腺激素依赖的CYP 5表达 ...更多信息 1定位于丘和靠近卵母细胞的颗粒细胞支持这种可能性。肝脏CYP 51的表达依赖于胰岛素。胰岛素的增强作用是通过其对SREBP-1c的诱导作用来解释的，就像其他脂质代谢酶一样。提示肝细胞色素P451的表达可能作为脂代谢酶的一员而受到调控。肝脏、小肠和肾上腺中CYP 51的表达也受甲状腺激素的影响。地塞米松（dexamethazone，dex）可抑制甲状腺激素依赖性CYP 51的表达，并降低肝脏、小肠和肾上腺中CYP 51的含量。剂量反应实验表明糖皮质激素受体参与地塞米松抑制CYP 51表达的作用。在脑和肝中CYP 51表达的激素调节之间未观察到实质性差异。SER、CRE和GCAAT元件对CYP 51表达的重要作用也被提出。少

项目成果

吉田雄三, 青山由利: "P450の分子生物学(大村, 石村, 藤井編) コレステロール生合成系"講談社サイエンティフィク. 255 (2003)

Yuzo Yoshida、Yuri Aoyama：“P450 的分子生物学（Omura、Ishimura、Fujii 编辑）胆固醇生物合成系统”讲谈社科学 255（2003）。

Ji, H., Zhang, W., Zhang, M., Kudo, M., Aoyama, Y., Yoshida, Y.et al.: "Structure-based de novo design, synthesis, and biological evaluation of non-azole inhibitors specific for lanosterol 14alpha-demethylase of fungi"J. Med. Chem.. 46. 474-485 (2003)

Ji, H.、Zhang, W.、Zhang, M.、Kudo, M.、Aoyama, Y.、Yoshida, Y.等人：“基于结构的非唑类化合物的从头设计、合成和生物学评价