Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China.
Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Beijing, China.
Cell Biol Int. 2020 Dec;44(12):2427-2437. doi: 10.1002/cbin.11450. Epub 2020 Aug 31.
Benzo[a]pyrene (B[a]P), a potent carcinogen, has been proved that it can induce apoptosis via activation of the aryl hydrocarbon receptor (AhR) pathway. The metabolite of tryptophan 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous activator of AhR, plays bifunctional roles in cell growth and apoptosis. However, whether and how FICZ can reduce the toxicity of B[a]P and the mechanism underlying this remain unclear. In this study, FICZ interfered with the toxicity of B[a]P in mouse hepatocarcinoma cell line Hepa1-6. The results of the MTT assay indicated that FICZ and B[a]P made opposite effects on cell proliferation. The scratch-wound healing assay showed that B[a]P (1 µM for 24 hr) exposure triggered cell migration and that was inhibited by FICZ (10 nM). In addition, FICZ ameliorated B[a]P-induced apoptosis by inhibiting reactive oxygen species generation and caspase-3 activation, as well as increasing reduced glutathione level in mitochondria. Furthermore, gene expression analyses indicated that FICZ competed with B[a]P, which reduced the transcriptional activation of the cyp1a1 and cyp1b1 genes, as well as Bcl2 and P53. Accordingly, the interaction between FICZ and B[a]P in the AhR pathway inhibited apoptosis in a mitochondrial-dependent manner, suggesting that endogenous compound may reduce the toxicity of exogenous pollutant in vivo and providing an available way to improve health condition related to the hepatic metabolic disorder.
苯并[a]芘（B[a]P）是一种强致癌物质，已被证明可通过激活芳香烃受体（AhR）途径诱导细胞凋亡。色氨酸代谢物 6-甲酰基吲哚并[3,2-b]咔唑（FICZ）是 AhR 的内源性激活剂，在细胞生长和凋亡中发挥双重作用。然而，FICZ 是否以及如何降低 B[a]P 的毒性及其潜在机制尚不清楚。在本研究中，FICZ 干预了苯并[a]芘对小鼠肝癌细胞系 Hepa1-6 的毒性。MTT 检测结果表明，FICZ 和 B[a]P 对细胞增殖的作用相反。划痕愈合实验表明，B[a]P（1 μM 作用 24 小时）暴露可触发细胞迁移，而 FICZ（10 nM）可抑制细胞迁移。此外，FICZ 通过抑制活性氧生成和半胱天冬酶-3 的激活以及增加线粒体中还原型谷胱甘肽水平来减轻 B[a]P 诱导的细胞凋亡。此外，基因表达分析表明，FICZ 与 B[a]P 竞争，降低了 cyp1a1 和 cyp1b1 基因以及 Bcl2 和 P53 的转录激活。因此，FICZ 与 B[a]P 在 AhR 通路中的相互作用以线粒体依赖性方式抑制细胞凋亡，表明内源性化合物可能降低体内外源性污染物的毒性，并为改善与肝脏代谢紊乱相关的健康状况提供了一种可行的方法。
