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

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

doi:10.1016/j.fct.2023.114048

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

Food Chem Toxicol. 2023 Oct:180:114048. doi: 10.1016/j.fct.2023.114048. Epub 2023 Sep 19.

Authors

Haoyang Zou¹, Jia Yu¹, Zhuolin Li², Yao Liu³, Tuoyi Wang³, Tiezhu Li², Chengyu Lv², Jie Zhang⁴

Affiliations

¹ College of Food Science and Engineering, Jilin University, Changchun, 130062, China.
² Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Changchun, 130033, China.
³ College of Food and Bioengineering, Qiqihar University, Qiqihar, 161006, China.
⁴ College of Food Science and Engineering, Jilin University, Changchun, 130062, China. Electronic address: zhangjie83@jlu.edu.cn.

PMID: 37734465
DOI: 10.1016/j.fct.2023.114048

Abstract

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. 3,6-Dibromocarbazole reduced the expression levels of glucocorticoid responsive genes including glucose-6-phosphatase (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-pituitary-adrenocortical (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.

Keywords: 3,6-Dibromocarbazole; Antagonist activity; Glucocorticoid receptor; Zebrafish.