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

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 (LXRα 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.

► We identified EDCs which enhanced SXR-mediated transactivation of CYP3A and CYP7A1. ► Positive EDCs activated transactivation of CYP3A2 and CYP3A4 via SXR nearly evenly. ► SXR produced fluorescence foci in nucleus with the treatment of ligands. ► Endogenous CYP3A4 mRNA expression was enhanced by positive EDCs.