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- Title
PII-22.
- Authors
Krasowski, M. D.; Reschly, E. J.; Iyer, M.
- Abstract
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
- Subjects
PHARMACEUTICAL research; PREGNANE; STEROIDS; HORMONE receptors; PHARMACOLOGY; BILE salts
- Publication
Clinical Pharmacology & Therapeutics, 2006, Vol 79, Issue 2, pP42
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1016/j.clpt.2005.12.147