使用人类雌激素受体α模拟的强度值的生理和生化基础:用于识别内分泌干扰物的含义
Christopher J Borgert1, Lyle D Burgoon2, John C Matthews3
1Applied Pharmacology and Toxicology, Inc. and CEHT, Univ. FL College of Vet. Med., Gainesville, FL, USA. cjborgert@apt-pharmatox.com.
对于雌激素受体-α (ERα) 连接体的人类相关的强度值是由身体的自然代谢物质决定的. 干必须至少比这个值强10倍,才能破坏雌激素通路.
科学领域:
- 内分泌学 在内分泌学.
- 分子药理学分子药理学
- 毒理学 毒理学 毒理学
背景情况:
- 内分泌系统依赖于连接体-受体相互作用,其中连接体的强度 (亲和力 × 疗效) 和度决定了生理效应.
- 对于雌激素受体α (ERα) 激动剂的先前确定的人类相关值 (HRPT) 是10-4相对于17β-雌激醇 (E2),在此以下不会产生临床可观测的雌激素效应.
- 内生代谢环境,包括激素前体和代谢物,可能会影响这种HRPT.
研究的目的:
- 测试假设,ERα HRPT是由内源性ERα配体的正常代谢环境中的受体占用而建立的.
- 为了确定ERα连接体是否可以与内源成分竞争,以在人类血液中发现的度下与受体结合.
- 基于分子动力学,为ERα HRPT提供一种机械解释.
主要方法:
- 计算了不同强度的ERα配体的分数受体占用率.
- 在生理度下对ERα占用率与单个内源性配体和混合物进行竞争的评估.
- 利用已确定的质量作用规律和已知的内源ERα配体的特性.
主要成果:
- 具有强度大于HRPT的十倍 (10-3相对于E2) 的ERα配体可以成功地与内源成分竞争受体占用.
- 功率小于HRPT的十倍的干不能有效地竞争ERα结合.
- 已经证明,内源代谢环境对观察到的ERα激动剂HRPT.负责.
结论:
- 之前提出的ERα HRPT (10-4相对于E2) 是保守的,这表明有强有力的证据表明,在这个值以下的配体对雌激素途径的破坏.
- 与E2相比,强度为10-3的化学物质需要证据来评估内分泌干扰潜力.
- HRPT适用于ERα激动剂和抗剂,提供基于分子动力学和内源代谢的机理解释.
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