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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons
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Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons

机译：成年雄性大鼠海马通过神经元中定位的细胞色素P45017α和P450芳香化酶从孕烯醇酮合成雌二醇

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In adult mammalian brain, occurrence of the synthesis of estradiol from endogenous cholesterol has been doubted because of the inability to detect dehydroepiandrosterone synthase, P45017α. In adult male rat hippocampal formation, significant localization was demonstrated for both cytochromes P45017α and P450 aromatase, in pyramidal neurons in the CA1-CA3 regions, as well as in the granule cells in the dentate gyrus, by means of immunohistochemical staining of slices. Only a weak immunoreaction of these P450s was observed in astrocytes and oligodendrocytes. ImmunoGold electron microscopy revealed that P45017α and P450 aromatase were localized in pre- and postsynaptic compartments as well as in the endoplasmic reticulum in principal neurons. The expression of these cytochromes was further verified by using Western blot analysis and RT-PCR. Stimulation of hippocampal neurons with N-methyl-D-aspartate induced a significant net production of estradiol. Analysis of radioactive metabolites demonstrated the conversion from [~3H]pregnenolone to ~3H]estradiol through dehydroepiandrosterone and testosterone. This activity was abolished by the application of specific inhibitors of cytochrome P450s. Interestingly, estradiol was not significantly converted to other steroid metabolites. Taken together with our previous finding of a P450scc-containing neuronal system for pregnenolone synthesis, these results imply that 17β-estradiol is synthesized by P45017α and P450 aromatase localized in hippocampal neurons from endogenous cholesterol. This synthesis may be regulated by a glu-tamate-mediated synaptic communication that evokes Ca~(2+) signals.
机译：在成年哺乳动物的大脑中，由于无法检测到脱氢表雄甾酮合酶P45017α，人们怀疑内源性胆固醇合成雌二醇的发生。在成年雄性大鼠海马区的形成中，通过切片的免疫组织化学染色，证明了细胞色素P45017α和P450芳香化酶在CA1-CA3区的锥体神经元以及齿状回的颗粒细胞中都有明显的定位。在星形胶质细胞和少突胶质细胞中仅观察到这些P450的弱免疫反应。 ImmunoGold电子显微镜检查显示P45017α和P450芳香化酶位于主要神经元的突触前和突触后隔室以及内质网中。通过使用蛋白质印迹分析和RT-PCR进一步验证了这些细胞色素的表达。用N-甲基-D-天冬氨酸刺激海马神经元诱导大量的雌二醇净产生。放射性代谢产物分析表明，[〜3H]孕烯醇酮通过脱氢表雄酮和睾丸酮转化为〜3H]雌二醇。通过使用细胞色素P450的特异性抑制剂，该活性被取消。有趣的是，雌二醇并未显着转化为其他类固醇代谢产物。结合我们先前发现的用于孕烯醇酮合成的含有P450scc的神经元系统的发现，这些结果表明17β-雌二醇是由内源性胆固醇中位于海马神经元中的P45017α和P450芳香化酶合成的。该合成可以通过唤起Ca〜（2+）信号的谷氨酸盐介导的突触通信来调节。

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