在肺气道爆炸模型中纳夫他林-DNA附带形成:生物激活和纳夫他林代谢物的作用
Morgan C Domanico1, Sarah A Carratt1, Nicole Collette2
1Center for Health and the Environment, University of California Davis, Davis, California 95616, United States.
Chemical research in toxicology
|February 23, 2026
概括
暴露在纳夫他林中会形成有毒代谢物,损害肺细胞. 这项研究表明,这些代谢物和甲本身在小鼠和灵长类动物的肺部中产生持久的DNA附加物,这表明人类的基因毒性风险.
科学领域:
- 毒理学 毒理学 毒理学
- 遗传学 是一个遗传学.
- 环境健康 环境健康
背景情况:
- 人类广泛接触到纳夫他,这种化合物会被代谢成对肺上皮细胞有害的有毒物质.
- 纳法代谢物在血液中循环,慢性暴露与肺部和鼻子病变有关,但基因毒性机制尚未完全理解.
- 基因组毒性的一个关键指标是DNA adduct形成,但不同纳甲产物在这个过程中的特定作用需要进一步调查.
研究的目的:
- 研究纳夫他林及其代谢物对肺组织中DNA adduct形成的影响.
- 在小鼠和灵长类动物的肺部实验中比较纳夫他林代谢物的基因毒性作用.
- 为了确定参与纳夫他林诱导的DNA adduct形成的酶途径.
主要方法:
- 从小鼠和灵长类动物的肺部进行微切割的导管气道爆炸物被用放射性标记的甲,1,2-甲基或甲-1,2-二二醇化.
- 在早期 (1小时) 和晚期 (24小时) 的时间点分析了探索物,以测量14C纳入DNA的时间点.
- 使用加速器质谱法量化DNA附加物形成,并使用基因淘汰模型 (Cyp2abfgs) 来评估特定酶的作用.
主要成果:
- 这三种放射性标记化合物 (纳夫他林,1,2-纳夫托金,纳夫他林-1,2-二二醇) 都在24小时内形成了DNA附加物.
- 缺少Cyp2abfgs基因的小鼠显示,乙烯诱导的DNA附加物显著减少 (约4倍),使这些酶参与了这个过程.
- 由纳夫他林-1,2-二二醇形成的DNA附加物在24小时内持续存在,并且附加物水平在小鼠和灵长类肺部扩展物之间是可比的.
结论:
- 纳法及其代谢物,包括纳法-1,2-二二醇,可以直接导致肺组织中持续的DNA adduct形成.
- 细胞P450酶的Cyp2abfgs子家族在纳夫他林诱导的DNA adduct形成中发挥着重要作用.
- 这些发现表明,甲烯及其活体代谢物的潜在基因毒性机制与动物和非人类灵长类动物,以及可能的人类相关.
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