title: Identification of endocrine disrupting chemicals activating SXR-mediated transactivation of CYP3A and CYP7A1.
abstract: 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.
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110001, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhou
authors.forename: Shuyan
authors.initials: S
authors.lastname: Cong
authors.forename: Shiying
authors.initials: S
authors.lastname: Sun
authors.forename: Hongmiao
authors.initials: H
authors.lastname: Sun
authors.forename: Renlong
authors.initials: R
authors.lastname: Zou
authors.forename: Shengli
authors.initials: S
authors.lastname: Wang
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
authors.forename: Jiao
authors.initials: J
authors.lastname: Jiao
authors.forename: Kiminobu
authors.initials: K
authors.lastname: Goto
authors.forename: Hajime
authors.initials: H
authors.lastname: Nawata
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D052244:Endocrine Disruptors / Q000494:pharmacology* / Q000633:toxicity; D017930:Genes, Reporter / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000071518:Liver X Receptors; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011987:Receptors, Steroid / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D052244:Endocrine Disruptors; D000071518:Liver X Receptors; D008565:Membrane Proteins; C000605213:NR1H3 protein, human; C000625852:NR1I2 protein, human; C000605215:Nr1h3 protein, rat; C000625854:Nr1i2 protein, rat; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D011994:Recombinant Proteins; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C532838:CYP7A1 protein, rat; D002790:Cholesterol 7-alpha-Hydroxylase; C510163:CYP3A4 protein, human