title: Activation of steroid and xenobiotic receptor (SXR, NR1I2) and its orthologs in laboratory, toxicologic, and genome model species.
abstract: BACKGROUND
  Nuclear receptor subfamily 1, group I, member 2 (NR1I2), commonly known as steroid and xenobiotic receptor (SXR) in humans, is a key ligand-dependent transcription factor responsible for the regulation of xenobiotic, steroid, and bile acid metabolism. The ligand-binding domain is principally responsible for species-specific activation of NR1I2 in response to xenobiotic exposure.
  
  
  OBJECTIVE
  Our objective in this study was to create a common framework for screening NR1I2 orthologs from a variety of model species against environmentally relevant xenobiotics and to evaluate the results in light of using these species as predictors of xenobiotic disposition and for assessment of environmental health risk.
  
  
  METHODS
  Sixteen chimeric fusion plasmid vectors expressing the Gal4 DNA-binding domain and species-specific NR1I2 ligand-binding domain were screened for activation against a spectrum of 27 xenobiotic compounds using a standardized cotransfection receptor activation assay.
  
  
  RESULTS
  NR1I2 orthologs were activated by various ligands in a dose-dependent manner. Closely related species show broadly similar patterns of activation; however, considerable variation to individual compounds exists, even among species varying in only a few amino acid residues.
  
  
  CONCLUSIONS
  Interspecies variation in NR1I2 activation by various ligands can be screened through the use of in vitro NR1I2 activation assays and should be taken into account when choosing appropriate animal models for assessing environmental health risk.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Milnes
authors.forename: Adriana
authors.initials: A
authors.lastname: Garcia
authors.forename: Emily
authors.initials: E
authors.lastname: Grossman
authors.forename: Felix
authors.initials: F
authors.lastname: Grün
authors.forename: Jason
authors.initials: J
authors.lastname: Shiotsugu
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Tabb
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kawashima
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Katsu
authors.forename: Hajime
authors.initials: H
authors.lastname: Watanabe
authors.forename: Taisen
authors.initials: T
authors.lastname: Iguchi
authors.forename: Bruce
authors.initials: B
authors.lastname: Blumberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D006801:Humans; D023421:Models, Animal; D008969:Molecular Sequence Data; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000235:genetics; D013045:Species Specificity; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D015262:Xenobiotics