In vitro, in vivo, and in silico evaluation of the glucocorticoid receptor antagonist activity of 3,6-dibromocarbazole

文献类型： 外文期刊

第一作者： Zou, Haoyang

作者： Zou, Haoyang;Yu, Jia;Zhang, Jie;Li, Zhuolin;Li, Tiezhu;Lv, Chengyu;Liu, Yao;Wang, Tuoyi

作者机构：

关键词： 3,6-Dibromocarbazole; Glucocorticoid receptor; Antagonist activity; Zebrafish

期刊名称：FOOD AND CHEMICAL TOXICOLOGY （ 影响因子：4.3； 五年影响因子：5.1 ）

ISSN： 0278-6915

年卷期： 2023 年 180 卷

页码：

收录情况： SCI

摘要： 3,6-Dibromocarbazole is a novel environmental contaminant which is currently detected in several environmental media worldwide. This work aims to investigate the anti-glucocorticoid potency and endocrine disrupting effects of 3,6-dibromocarbazole. In vitro experiments indicated that 3,6-dibromocarbazole possessed glucocorticoid receptor (GR) antagonistic activity and inhibited dexamethasone-induced GR nuclear translocation. 3,6Dibromocarbazole reduced the expression levels of glucocorticoid responsive genes including glucose-6phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), fatty acid synthase (FAS), and tyrosine aminotransferase (TAT), and further disrupted the protein expression of two key enzymes PEPCK and FAS in gluconeogenesis. In vivo experiments showed that 3,6-dibromocarbazole induced abnormal development of zebrafish embryos and disrupted the major neurohormones involved in activation of hypothalamic-pituitaryadrenocortical (HPA) axis in zebrafish larvae. The results of molecular docking and molecular dynamics simulation contributed to explain the antagonistic effect of 3,6-dibromocarbazole. Taken together, this work identified 3,6-dibromocarbazole as a GR antagonist, which might exert endocrine disrupting effects by interfering the pathway of gluconeogenesis.

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