Benzoate X receptors α and β are pharmacologically distinct and do not function as xenobiotic receptors

Abstract

The Xenopus benzoate nuclear hormone receptors, BXRα and BXRβ, 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 BXRα and BXRβ are pharmacologically distinct from each other: BXRα is more promiscuous than BXRβ with respect to both ligand specificity and co-activator recruitment. BXRα 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, BXRα-specific agonists such as 4-ABB, chlorpyrifos, and trifluralin act as antagonists on BXRβ. BXRs are widely distributed in adult tissues but do not show any enrichment in liver and intestine, major sites of SMR/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.