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在生物转化后,gefitinib的细胞光 (基因) 毒性

Meryem El Ouardi^1,2, Lorena Tamarit^1,2, Ignacio Vayá^1,2

¹Departamento de Química-Instituto de Tecnología Química UPV-CSIC, Universitat Politècnica de València, Valencia, Spain.

Frontiers in pharmacology

|June 23, 2023

概括

格菲提尼布的代谢物表现出不同的光毒性. O-Demorpholinopropyl gefitinib (DMOR-GFT) 具有高度的光毒性,而O-Demethyl gefitinib (DMT-GFT) 则表现出显著的光毒性潜力,导致DNA损伤.

科学领域:

药理学药理学是指药理学的学科.
摄影生物学摄影生物学
毒理学毒理学毒理学

背景情况:

格菲提尼布 (GFT) 是非小细胞肺癌的EGFR抑制剂,经过肝脏代谢产生反应性代谢物.
像O-Demethyl gefitinib (DMT-GFT),4-Defluoro-4-hydroxy gefitinib (DF-GFT) 和O-Demorpholinopropyl gefitinib (DMOR-GFT) 这样的代谢物具有增强的紫外线吸收能力.

研究的目的:

为了研究gefitinib代谢物的光敏化潜力.
阐明基菲提尼布代谢物引起的光敏感性背后的机制.

主要方法:

中性红色吸收 (NRU) 测定光毒性.
酸反应物质 (TBARS) 测定脂质光氧化.
2,4-Dinitrophenylhydrazine (DNPH) 衍生物化用于蛋白质光氧化.
对DNA损伤进行彗星测定.

主要成果:

DF-GFT显示没有光毒性 (PIF ≈1). DMOR-GFT具有高度的光毒性 (PIF = 48),而DMT-GFT则较少 (PIF = 7).
DMOR-GFT诱导了显著的脂质光氧化. GFT和DMOR-GFT导致蛋白质光氧化;DMT-GFT的影响很小.
DMT-GFT表现出最高的光遗传毒性潜力,诱导修复不良的DNA损伤,暗示了变种/致癌风险.

结论:

格菲提尼布代谢物表现出不同的光毒性和机制.
DMOR-GFT具有显著的光敏感性风险,而DMT-GFT则存在光原毒性问题.
这些发现支持瘤学家对TKI使用,光保护和患者管理的指导.

关键词:

抗癌药物是一种抗癌药物.代谢代谢代谢代谢对生物分子的光损伤.光敏感反应反应的发生.氨酸激酶抑制剂氨酸激酶抑制剂

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