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PII‐22
Author(s) -
Krasowski M. D.,
Reschly E. J.,
Iyer M.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.147
Subject(s) - pregnane x receptor , calcitriol receptor , in silico , steroid , receptor , nuclear receptor , ligand (biochemistry) , chemistry , steroid hormone , pregnane , pharmacology , dihydrotestosterone , hormone , constitutive androstane receptor , biochemistry , biology , stereochemistry , transcription factor , androgen , gene
BACKGROUND/AIMS The pregnane X receptor (PXR; NR1I2) is a nuclear hormone receptor with broad ligand specificity that regulates the metabolism and elimination of bile salts, steroid hormones, and xenobiotics. PXR is closely related to the vitamin D receptor (VDR; NR1I1), although VDR has much narrower ligand specificity. The purpose of the study was to compare structure‐activity relationships for activation of the human PXR and VDR by 47 bile salts and 71 steroid hormones and to use in silico modeling to determine the role of ligand‐binding pocket size, ligand orientation, and receptor flexibility in determining ligand activity. METHODS Activation of human PXR and human VDR was studied using an in vitro assay in HepG2 liver cells. In silico modeling of human PXR ligand activation was performed with 4D‐QSAR analysis (Chem21 Group, Inc.) and comparative molecular field analysis (SYBYL with CoMFA, Tripos, Inc.). RESULTS Human PXR was activated by 25/47 bile salts and 58/71 steroids tested while human VDR was only activated by 5 bile salts. The concentrations of bile salts and steroids that activate human PXR are at least one, and often several, orders of magnitude higher than concentrations circulating in plasma in healthy humans. CONCLUSIONS Human PXR has very broad specificity but low affinity for bile salts and steroid compounds, consistent with a role in detecting toxic levels of these compounds. This broad specificity present significant challenges for in silico prediction of human PXR ligand activation. Clinical Pharmacology & Therapeutics (2005) 79 , P42–P42; doi: 10.1016/j.clpt.2005.12.147