Activation of steroid and xenobiotic receptor (SXR, NR1I2) and its orthologs in laboratory, toxicologic, and genome model species.
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.
Milnes
Matthew R
MR
Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300, USA.
Garcia
Adriana
A
Grossman
Emily
E
Grün
Felix
F
Shiotsugu
Jason
J
Tabb
Michelle M
MM
Kawashima
Yukio
Y
Katsu
Yoshinao
Y
Watanabe
Hajime
H
Iguchi
Taisen
T
Blumberg
Bruce
B
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*
C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D015262:Xenobiotics