Benzoate X receptors alpha and beta are pharmacologically distinct and do not function as xenobiotic receptors.
The Xenopus benzoate nuclear hormone receptors, BXRalpha and BXRbeta, share 82% identity within their ligand-binding domains and are classified as members of the NR1I2 subfamily that includes the mammalian steroid and xenobiotic receptor, SXR/PXR. Although alkyl benzoates have been identified as endogenous ligands, the exact role of the benzoate receptors in amphibian physiology has not been established. In this report, we show that BXRalpha and BXRbeta are pharmacologically distinct from each other: BXRalpha is more promiscuous than BXRbeta with respect to both ligand specificity and co-activator recruitment. BXRalpha can be transactivated by a number of benzoate derivatives including 4-amino-butylbenzoate (4-ABB), 4-hydroxy-butylbenzoate (4-HBB), 3-hydroxy ethyl benzoate (3-HEB), and benzyl benzoate, but only 4-HBB acts as an agonist for both receptors. Furthermore, BXRalpha-specific agonists such as 4-ABB, chlorpyrifos, and trifluralin act as antagonists on BXRbeta. BXRs are widely distributed in adult tissues but do not show any enrichment in liver and intestine, major sites of SXR/PXR expression that are critical in xenobiotic metabolism. Neither BXR shows the broad specificity toward steroids or xenobiotics exhibited by SXR/PXR. Therefore, we conclude that the BXRs are pharmacologically distinct from each other and unlikely to serve as xenobiotic sensors.
Department of Developmental and Cell Biology, University of California, Irvine 92697-2300, USA.
Felix
F
Grün
Ranga N
RN
Venkatesan
Michelle M
MM
Tabb
Changcheng
C
Zhou
Junran
J
Cao
Daniel
D
Hemmati
Bruce
B
Blumberg
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001566:Benzocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019556:COS Cells; D004390:Chlorpyrifos / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D010226:Parabens / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D014018:Tissue Distribution; D014162:Transfection; D014274:Trifluralin / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D015262:Xenobiotics / Q000494:pharmacology; D014981:Xenopus; D029867:Xenopus Proteins
D001565:Benzoates; D018076:DNA, Complementary; D008024:Ligands; D010226:Parabens; D018160:Receptors, Cytoplasmic and Nuclear; D015262:Xenobiotics; D029867:Xenopus Proteins; C112210:benzoate X receptor, Xenopus; C038091:butylparaben; D012313:RNA; D014274:Trifluralin; C004605:butamben; D004390:Chlorpyrifos; D001566:Benzocaine