Identification of endocrine disrupting chemicals activating SXR-mediated transactivation of CYP3A and CYP7A1

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• 作者：Tingting Zhou^a ; ¹ ; Shuyan Cong^b ; ¹ ; Shiying Sun^a ; Hongmiao Sun^a ; Renlong Zou^a ; Shengli Wang^a ; Chunyu Wang^a ; Jiao Jiao^a ; Kiminobu Goto^c ; Hajime Nawata^d ; Toshihiko Yanase^e ; Yue Zhao^a ; ^{zhaoyue@mail.cmu.edu.cn}
• 关键词：EDCs ; endocrine disrupting chemicals/environmental endocrine disrupters ; SXR ; steroid xenobiotic receptor in human ; PXR ; pregnane X receptor in rodent (rodent homologue of SXR) ; PAR ; pregnane activated receptor ; LXR¦Á ; liver X receptor alpha ; FXR ; farneso
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2013
• 出版时间：5 January, 2013
• 年：2013
• 卷：365
• 期：1
• 页码：36-43
• 全文大小：1014 K

文摘

Endocrine disrupting chemicals (EDCs) have emerged as a major public health issue because of their potentially disruptive effects on physiological hormonal actions. SXR (steroid xenobiotic receptor), also known as NR1I2, regulates CYP3A expression in response to exogenous chemicals, such as EDCs, after binding to SXRE (SXR response element). In our study, luciferase assay showed that 14 out of 55 EDCs could enhance SXR-mediated rat or human CYP3A gene transcription nearly evenly, and could also activate rat CYP7A1 gene transcription by cross-interaction of SXR and LXRE (LXR¦Á response element). SXR diffused in the nucleus without ligand, whereas intranuclear foci of liganded SXR were produced. Furthermore, endogenous mRNA expression of CYP3A4 gene was enhanced by the 14 positive EDCs. Our results suggested a probable mechanism of EDCs disrupting the steroid or xenobiotic metabolism homeostasis via SXR.