在体和体外多重分析方法用于选天然衍生的配体,用于红海的烯碳化合物受体
Jong-In Choi1, Woo-Seon Song2, Dong-Hee Koh2
1Department of Biology, Kyung Hee University, Seoul, Republic of Korea.
Ecotoxicology and environmental safety
|April 3, 2024
概括
研究人员开发了一种新的选方法,以预测海洋鱼类中的基碳化合物受体 (AHR) 活性. 这种方法使用in silico和in vitro数据来识别天然的AHR配体,这对于理解鱼类毒理学和开发更安全的化学品至关重要.
科学领域:
- 环境毒理学环境毒理学
- 分子药理学分子药理学
- 海洋生物学 海洋生物学
背景情况:
- 基碳化合物受体 (AHR) 是一种转录因子,介导有毒化合物效应,与自然配体如黄类药物显示在炎症和抗癌过程中的调节作用.
- 自然的AHR配体在野生动物,特别是鱼类中积累,但它们的多样性结构和海洋鱼类的特定AHR反应仍未得到充分研究.
- 开发新的选方法对于评估海洋鱼类中的各种天然AHR配体至关重要,考虑到物种特定的AHR特征.
研究的目的:
- 开发一种用于选激活红海AHR1和AHR2 (rsAHR1和rsAHR2) 的潜在天然配体的预测模型.
- 通过使用红海作为模型,研究海洋鱼类中各种天然AHR配体的转录活性和异型特异性.
- 通过将in silico和in vitro数据与大型毒理数据库相结合,建立一个强大的查方法.
主要方法:
- 在COS-7细胞中构建了rsAHR1和rsAHR2的体外记者基因测定,以测量10个自然AHR配体的转录活性.
- 开发了rsAHR1和rsAHR2联体结合域 (LBDs) 的in silico同质模型,以计算自然联体和二氧化的对接能量 (U_dock).
- 使用Tox21大数据验证预测模型,分析对接能量与人类AHR活动对一个大型化学库进行对接.
主要成果:
- FICZ,Genistein,Daidzein,I3C,DIM,Quercetin和Baicalin诱导了rsAHR1和rsAHR2的转录活性,对I3C,Baicalin,DIM和Quercetin观察到不同的异型特异性反应.
- 在rsAHR1 (R2=0.74) 和rsAHR2 (R2=0.83) 的in silico对接能量和体外转录活性 (EC50) 之间发现了显著的相关性,验证了同源模型.
- 在模型有效地区分使用U_dock值的活性和非活性化合物,并显示与来自Tox21数据库的人类AHR活动的相关性 (R2=0.45).
结论:
- 该研究成功开发并验证了一种用于选海洋鱼类,特别是红海中的天然AHR配体的in silico模型.
- 开发的模型提供了方程来定量估计AHR交易,作为一个有价值的工具来评估海洋生态系统中的环境暴露风险.
- 这种集成的in silico/in vitro方法提供了一种新的,有效的方法来识别潜在的AHR激动剂,并了解它们对海洋鱼类的毒理影响.
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