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

CYP2B亚家族在肝脏中呈结构性和性别二型性表达。在小鼠中，雌性表达远高于雄性，雄性(Crp2b10&Gt；Cyp2b9)和雌性(Cyp2b9&Gt；Cyp2b10)的表达种类不同。这些物种的表达可被苯巴比妥(PB)诱导，其诱导机制在分子水平上已被广泛揭示。女性激素和糖皮质激素可能分别参与Cyp2b9和Cyp2b10的表达，而后者同时抑制Cyp2b9的表达。男性激素的作用也被认为是抑制Cyp2b9的表达。荧光素酶分析表明，Cyp2b10基因5‘侧翼区-2331~-2281bp的序列与雌二醇的诱导有关。该区域对应于PB反应增强子模块(PBREM)的核心元件。PBREM核心元件的几个核苷酸突变表明，雌激素诱导所需的NR1(核受体1)位点与PB诱导所需的元件相同。该元件对DDT的诱导也起着关键作用，表明NR1位点对结构不同的诱导剂有反应。虽然Cyp2b9是在雌性肝脏中表达的主要物种，但其表达机制尚不清楚，但雌二醇被发现是研究该调控途径的有效诱导剂。

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.