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首页> 外文期刊>Journal of mass spectrometry: JMS >Trace LC/MS/MS quantitation of 17 beta-estradiol as a biomarker for selective estrogen receptor modulator activity in the rat brain
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Trace LC/MS/MS quantitation of 17 beta-estradiol as a biomarker for selective estrogen receptor modulator activity in the rat brain

机译：痕量LC / MS / MS定量检测17β-雌二醇作为大鼠脑中选择性雌激素受体调节剂活性的生物标志物

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A sensitive LC/MS/MS method has been developed by derivatization of 17 beta-estradiol (E2) with dansyl chloride to quantitate 17 beta-E2 in female rat serum. The use of E2-d(5) minimized interferences from endogenous 17 beta-E2 in order to achieve a limit of quantitation (LOQ) of 2.5 pg/ml using 150 mu l of female rat serum. The recovery of the dansyl derivative was 95% or greater in quality control samples. The intra and interday assay precision was better than 8.2 and 6.2%, respectively, with accuracies ranging from 97 to 101% in the quality control samples. The assay was used for the quantitation of serum E2 as a biomarker for the estrogen receptor (ER) antagonist activity of small molecule SERMs (selective estrogen receptor modulators) in the female rat brain. The study revealed that a statistically significant upregulation of serum 17 beta-E2 occurred for rats dosed with SERMs that are known to penetrate the brain and disrupt the hypothalamic-pituitary-ovarian (HPO) axis. Variations in 17 beta-E2 in ascending dose studies also correlated with the corresponding trends in CYP17a1 levels, an mRNA biomarker for ovarian hyperstimulation. This biomarker assay has provided a useful screen for medicinal chemistry optimization to produce SERMs that do not interfere with negative feedback of estrogens on the brain and for biological hypothesis testing.
机译：通过用丹磺酰氯衍生化17β-雌二醇（E2）以定量雌性大鼠血清中的17β-E2，已经开发出了一种灵敏的LC / MS / MS方法。使用E2-d（5）可最大程度地减少来自内源性17 beta-E2的干扰，以使用150μl雌性大鼠血清达到2.5 pg / ml的定量限（LOQ）。在质量控制样品中，丹磺酰基衍生物的回收率为95％或更高。日内和日间测定的准确度分别优于8.2％和6.2％，质量控制样品的准确度范围为97％至101％。该测定用于定量血清E2，作为雌性大鼠脑中小分子SERM（选择性雌激素受体调节剂）的雌激素受体（ER）拮抗剂活性的生物标记。这项研究表明，服用SERM的大鼠血清17β-E2在统计学上显着上调，已知该SERM可以穿透大脑并破坏下丘脑-垂体-卵巢（HPO）轴。递增剂量研究中17 beta-E2的变化也与CYP17a1水平的相应趋势相关，CYP17a1是卵巢过度刺激的一种mRNA生物标志物。该生物标志物测定法为药物化学优化提供了有用的筛选方法，以产生不会干扰脑部雌激素负反馈的SERM，并用于生物学假设测试。

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