EGFR和CYP信号干扰是6PPD-类肝毒性的基础:来自网络和机器学习方法的见解
Wenjie Zhang1, Banghua Wu1, Chengbin Hu2
1Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, China; School of Public Health, Sun Yat-sen University, Guangzhou, China.
一种来自轮胎的污染物N-(1,3-dimethylbutyl) -N'-phenyl-p-phenylenediamine quinone (6PPD-quinone) 通过抑制表皮生长因子受体 (EGFR) 信号传递和破坏细胞染色体P450 (CYP) 代谢,导致肝损伤.
科学领域:
- 环境毒理学环境毒理学
- 计算化学计算化学
- 分子生物学分子生物学
背景情况:
- 在人类样本中发现的一种新出现的环境污染物是N-(1,3-dimethylbutyl) -N'-phenyl-p-phenylenediamine quinone (6PPD-quinone).
- 6PPD-因与肝损伤有关,但其肝毒性机制尚不清楚.
研究的目的:
- 阐明6PPD-类诱导的肝毒性背后的分子机制.
- 确定潜在的治疗目标,以减轻不良健康影响.
主要方法:
- 集成在的方法:ADMET分析,网络毒理学,分子对接,分子动力学 (MD) 模拟和机器学习 (ML).
- 关键基因和蛋白质与蛋白质相互作用的识别.
- 评估6PPD-金对标蛋白的结合亲和力.
主要成果:
- 确定了62个关键交叉基因,与6PPD-类标和肝毒性相关.
- 揭示了两个主要的功能模块:EGFR介导的信号传递和CYP酶代谢.
- 通过ML分析证实了6PPD-胺与EGFR的强度结合及其强大的抑制作用.
- 证明了6PPD-氨酸6PPD-氨酸的多CYP酶抑制能力.
结论:
- 6PPD-因通过双重机制诱导肝损伤:抑制EGFR信号传递和破坏CYP介导的新陈代谢.
- 这项研究为评估轮胎衍生污染物的肝毒性风险提供了一个机制框架.
- 突出了EGFR和CYP酶作为干预的潜在目标.
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