6-Formylindolo[3,2-b]carbazole reduces apoptosis induced by benzo[a]pyrene in a mitochondrial-dependent manner
6-Formylindolo[3,2-b]carbazole reduces apoptosis induced by benzo[a]pyrene in a mitochondrial-dependent manner
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6-Formylindolo[3,2-b]咔唑以线粒体依赖性方式减少苯并[a]芘诱导的细胞凋亡
DOI：
10.1002/cbin.11450
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发表时间：
2020-08-31
影响因子：
3.9
通讯作者：
Chen, Gang
中科院分区：
文献类型：
--
作者：
Gan, Min;Ding, Hongbiao;Chen, Gang
苯并[a]芘（B[a]P）是一种强致癌物，已证实其可通过激活芳烃受体（AhR）途径诱导细胞凋亡。色氨酸的代谢产物6-甲酰吲哚并[3，2-B]咔唑（FICZ）是AhR的内源性激活剂，在细胞生长和凋亡中起着双重作用。然而，FICZ是否以及如何降低B[a]P的毒性及其机制尚不清楚。在这项研究中，FICZ干扰B[a]P在小鼠肝癌细胞系Hepa 1 -6中的毒性。MTT法结果显示FICZ和B[a]P对细胞增殖的作用相反。划痕伤口愈合试验表明，B[a]P（1 μ M，24小时）暴露引发细胞迁移，并被FICZ（10 nM）抑制。此外，FICZ改善B[a] P诱导的细胞凋亡，抑制活性氧的产生和caspase-3的激活，以及增加还原型谷胱甘肽水平在线粒体。此外，基因表达分析表明，FICZ与B[a]P竞争，从而降低了p1 a1和cyp 1b 1基因以及Bcl 2和P53的转录激活。因此，FICZ与B[a]P在AhR途径中的相互作用以细胞依赖的方式抑制细胞凋亡，提示内源性化合物可降低外源性污染物在体内的毒性，为改善与肝脏代谢紊乱相关的健康状况提供了一种有效途径。
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 mu M 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 thecyp1a1andcyp1b1genes, as well asBcl2andP53. 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.