Analysis of sex hormone-responsive element in sexually dimorphicly expressing CYP2B subfamily gene

CYP2B亚家族基因性二态性表达的性激素反应元件分析

• 批准号: 10672105
• 负责人: NEMOTO Nobuo
• 金额: $ 2.24万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672105/
• 关键词: CYP2B; Sex hormone; Glucocorticoid hormone; Phenobarbital; 肝細胞初代培養系; マウス肝細胞初代培養系

CYP2B subfamily constitutively and sexually dimorphicly expresses in the liver. In the mouse, the expression in female is far higher than that in male and the expressed species are different between male (Crp2b10>Cyp2b9) and female (Cyp2b9>Cyp2b10). The expression of these species is inducible by phenobarbital (PB), and the induction mechanism has been extensively revealed at molecular level. However, the mechanism of their constitutive expression has been scarcely investigated.Female and glucocorticoid hormones may participate the expression of Cyp2b9 and Cyp2b10, respecitively, and the latter hormone simultaneously suppresses Cyp2b9 expression. The role of male hormone is also considered to suppress Cyp2b9 expression. The sequence from -2331 to -2281 bp of the 5'-flanking region of Cyp2b10 gene is revealed to be responsible for the estradiol induction using luciferase assay. This region corresponds to the core element of PB-responsive enhancer module (PBREM). Several nucleotide mutations in the PBREM core element show that the NR1 (nuclear receptor 1) site is required for estradiol induction, the same element required for PB induction. The element also plays a critical role for induction by DDT, indicating that NR1 site responds to structurally-diversed inducers. Although Cyp2b9 is a major species expressed in female liver, no information is available for its expression mechanism, but estradiol is found as a potent inducer for investigating of the regulatory pathway.

CYP 2B亚家族在肝脏中组成型和性二型表达。在小鼠中，雌性的表达量远高于雄性，且表达种类在雄性（Crp 2b 10> Cyp 2b 9）和雌性（Cyp 2b 9> Cyp 2b 10）之间存在差异。这些物种的表达可被苯巴比妥（PB）诱导，其诱导机制已在分子水平上得到广泛揭示。雌激素和糖皮质激素可能分别参与Cyp 2b 9和Cyp 2b 10的表达，而Cyp 2b 10同时抑制Cyp 2b 9的表达。雄性激素的作用也被认为是抑制Cyp 2b 9表达。用荧光素酶法检测Cyp 2b 10基因5 ′侧翼区-2331 ~-2281bp的序列，发现该序列与雌二醇的诱导有关。该区域对应于PB响应增强子模块（PBREM）的核心元件。PBREM核心元件中的几个核苷酸突变表明，NR 1（核受体1）位点是雌二醇诱导所需的，与PB诱导所需的元件相同。该元素也起着关键作用的诱导DDT，表明NR 1位点响应于结构多样化的诱导剂。虽然Cyp 2b 9是在雌性肝脏中表达的主要物种，但没有关于其表达机制的信息，但发现雌二醇是研究调控途径的有效诱导剂。

项目成果

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Sakuma T 等人：“苯巴比妥在芳烃反应性和非反应性小鼠肝脏中的诱导”，《药物代谢处​​置》，第 27 卷，379-384。

Miyamoto M et al.: "CYP2A6 gene deletion reduces susceptibility to lung cancer."Biochem Biophys Res Commun. 261巻. 658-660 (1999)

Miyamoto M 等人：“CYP2A6 基因缺失降低了对肺癌的易感性。”Biochem Biophys Res Commun. 261. 658-660 (1999)

Chida M, Yokoi T, Nemoto N, Inaba M, Kinoshita M, Kamataki T.: "A new variant CYP2D6 allele(CYP2D6^*21) with a single base insertion in exon 5 in Japanese population associated with a poor metabolizer phenotype."Pharmacogenetics. 9. 287-293 (1999)

Chida M、Yokoi T、Nemoto N、Inaba M、Kinoshita M、Kamataki T.：“一种新的变异 CYP2D6 等位基因 (CYP2D6^*21)，在日本人群的外显子 5 中插入一个单碱基，与代谢不良表型相关。”