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B Alex Merrick1, Ashley M Brooks2, Julie F Foley1
1Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America.
PloS one
|December 3, 2025
概括
暴露于多环芳 (PAH),如酸 (BaP),可以导致DNA添加物和癌症. 即使有细胞防御,反应性BaP代谢物也可以穿越细胞膜,可能导致突变.
科学领域:
- 环境健康 环境健康
- 分子毒理学 分子毒理学
- 致癌的发生是致癌的产生.
背景情况:
- 多环芳 (PAH),如烯 (BaP),是环境致癌物,与瘤启动有关.
- 在BAP暴露后形成DNA和蛋白质添加物,其中谷氨酸S转移酶 (GST) 通过谷氨酸 (GSH) 结合在解毒中发挥作用.
- T47D乳腺细胞代谢BaP,产生细胞内和细胞外的添加物.
研究的目的:
- 为了研究细胞谷氨 (GSH) 水平与DNA和蛋白质添加物在BaP暴露后的形成之间的关系.
- 描述T47D细胞中BaP代谢产物及其添加物的形成和转移.
- 为了确定参与BaP生物活化和代谢的关键酶.
主要方法:
- T47D乳腺细胞被用布氨酸硫胺 (BSO) 或BaP治疗以改变GSH水平,随后暴露于3H-BaP.
- 在24-48小时内分析了吸管形成 (DNA,细胞蛋白,细胞外蛋白) 和代谢物概况.
- 基因表达分析 (生物信息学) 确定了参与BaP代谢的关键细胞染色体P450酶 (CYP1B1,CYP1A1).
主要成果:
- 在GSH水平和核蛋白/DNA添加物之间观察到一个逆相关性.
- 细胞外蛋白质添加物比细胞蛋白质添加物显著高 (5-10倍).
- 尽管有结合途径,但活性BaP代谢物 (例如,BPDE) 显示出稳定性和跨细胞膜转移到细胞外空间.
结论:
- 反应性BaP代谢物可以很容易地穿越细胞膜,即使有活跃的结合系统.
- 转位的BaP代谢物对邻近细胞的DNA结合和体质突变构成风险.
- 这突显了PAH暴露可能导致癌症发展的潜力,特别是在上皮组织中.
相关概念视频
01:26Toxic Reactions: Overview
When toxic substances penetrate the human body, they disseminate to various tissues, undergoing metabolic changes. This process yields reactive metabolites that may covalently bind with specific target molecules, resulting in toxicity.
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...
01:25Bioactivation and Tissue Toxicity
Bioactivation is a metabolic process that transforms less reactive substances into highly reactive metabolites, initiating tissue toxicity. This transformation can lead to various toxic effects, including carcinogenesis and teratogenesis. Reactive metabolites are classified into two main types: electrophiles and free radicals.Electrophiles are electron-deficient species and are produced primarily by the enzyme cytochrome P-450 during the metabolism of compounds containing carbon, nitrogen, or...