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Evolution of pharmacologic specificity in the pregnane X receptor.

Ekins S, Reschly EJ, Hagey LR, Krasowski MD - BMC Evol. Biol. (2008)

Bottom Line: In addition, we compared in detail the selectivity of human and zebrafish PXRs for steroidal compounds and xenobiotics.In contrast to other nuclear hormone receptors, PXRs show significant differences in ligand specificity across species.The Western clawed frog PXR, like that described for African clawed frog PXRs, has diverged considerably in ligand selectivity from fish, bird, and mammalian PXRs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Collaborations in Chemistry, Inc., Jenkintown, PA, USA. ekinssean@yahoo.com

ABSTRACT

Background: The pregnane X receptor (PXR) shows the highest degree of cross-species sequence diversity of any of the vertebrate nuclear hormone receptors. In this study, we determined the pharmacophores for activation of human, mouse, rat, rabbit, chicken, and zebrafish PXRs, using a common set of sixteen ligands. In addition, we compared in detail the selectivity of human and zebrafish PXRs for steroidal compounds and xenobiotics. The ligand activation properties of the Western clawed frog (Xenopus tropicalis) PXR and that of a putative vitamin D receptor (VDR)/PXR cloned in this study from the chordate invertebrate sea squirt (Ciona intestinalis) were also investigated.

Results: Using a common set of ligands, human, mouse, and rat PXRs share structurally similar pharmacophores consisting of hydrophobic features and widely spaced excluded volumes indicative of large binding pockets. Zebrafish PXR has the most sterically constrained pharmacophore of the PXRs analyzed, suggesting a smaller ligand-binding pocket than the other PXRs. Chicken PXR possesses a symmetrical pharmacophore with four hydrophobes, a hydrogen bond acceptor, as well as excluded volumes. Comparison of human and zebrafish PXRs for a wide range of possible activators revealed that zebrafish PXR is activated by a subset of human PXR agonists. The Ciona VDR/PXR showed low sequence identity to vertebrate VDRs and PXRs in the ligand-binding domain and was preferentially activated by planar xenobiotics including 6-formylindolo-[3,2-b]carbazole. Lastly, the Western clawed frog (Xenopus tropicalis) PXR was insensitive to vitamins and steroidal compounds and was activated only by benzoates.

Conclusion: In contrast to other nuclear hormone receptors, PXRs show significant differences in ligand specificity across species. By pharmacophore analysis, certain PXRs share similar features such as human, mouse, and rat PXRs, suggesting overlap of function and perhaps common evolutionary forces. The Western clawed frog PXR, like that described for African clawed frog PXRs, has diverged considerably in ligand selectivity from fish, bird, and mammalian PXRs.

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Chemical structures of PXR activators. Chemical structures of the PXR activators 5β-pregnane-3,20-dione, 5α-androstan-3α-ol, 5β-lithocholic acid, 5α-cyprinol 27-sulfate, 3-aminoethylbenzoate, and 6-formylindolo-[3,2-b]-carbozole. The key bond positions are numbered for the steroids and bile salts, and the lettering of the steroidal rings is indicated for pregnanedione and lithocholic acid. The structure to the right of lithocholic acid illustrates the most stable orientation of the A, B, and C steroid rings for 5β-bile salts (like lithocholic acid) with the A/B cis configuration (referring to the relative orientation of the hydrogen atom substituents on carbon atoms 5 and 10). The structure to the right of 5α-cyprinol sulfate shows the most stable orientation of 5α-bile salts (like 5α-cyprinol sulfate) that prefentially adopt the A/B trans configuration.
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Figure 1: Chemical structures of PXR activators. Chemical structures of the PXR activators 5β-pregnane-3,20-dione, 5α-androstan-3α-ol, 5β-lithocholic acid, 5α-cyprinol 27-sulfate, 3-aminoethylbenzoate, and 6-formylindolo-[3,2-b]-carbozole. The key bond positions are numbered for the steroids and bile salts, and the lettering of the steroidal rings is indicated for pregnanedione and lithocholic acid. The structure to the right of lithocholic acid illustrates the most stable orientation of the A, B, and C steroid rings for 5β-bile salts (like lithocholic acid) with the A/B cis configuration (referring to the relative orientation of the hydrogen atom substituents on carbon atoms 5 and 10). The structure to the right of 5α-cyprinol sulfate shows the most stable orientation of 5α-bile salts (like 5α-cyprinol sulfate) that prefentially adopt the A/B trans configuration.

Mentions: The pregnane X receptor (PXR; NR1I2; also known as steroid and xenobiotic receptor) is a member of the nuclear hormone receptor (NR) superfamily [1,2]. PXR functions as a ligand-activated transcription factor and regulates the metabolism, transport, and excretion of exogenous compounds, steroid hormones, vitamins, bile salts, and xenobiotics. A remarkably diverse array of compounds activate human PXR, although generally only at micromolar concentrations (less commonly at high nanomolar concentrations), consistent with a hypothesized function of PXR as a toxic compound sensor [3,4] (see Figure 1 for chemical structures of some PXR activators).


Evolution of pharmacologic specificity in the pregnane X receptor.

Ekins S, Reschly EJ, Hagey LR, Krasowski MD - BMC Evol. Biol. (2008)

Chemical structures of PXR activators. Chemical structures of the PXR activators 5β-pregnane-3,20-dione, 5α-androstan-3α-ol, 5β-lithocholic acid, 5α-cyprinol 27-sulfate, 3-aminoethylbenzoate, and 6-formylindolo-[3,2-b]-carbozole. The key bond positions are numbered for the steroids and bile salts, and the lettering of the steroidal rings is indicated for pregnanedione and lithocholic acid. The structure to the right of lithocholic acid illustrates the most stable orientation of the A, B, and C steroid rings for 5β-bile salts (like lithocholic acid) with the A/B cis configuration (referring to the relative orientation of the hydrogen atom substituents on carbon atoms 5 and 10). The structure to the right of 5α-cyprinol sulfate shows the most stable orientation of 5α-bile salts (like 5α-cyprinol sulfate) that prefentially adopt the A/B trans configuration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2358886&req=5

Figure 1: Chemical structures of PXR activators. Chemical structures of the PXR activators 5β-pregnane-3,20-dione, 5α-androstan-3α-ol, 5β-lithocholic acid, 5α-cyprinol 27-sulfate, 3-aminoethylbenzoate, and 6-formylindolo-[3,2-b]-carbozole. The key bond positions are numbered for the steroids and bile salts, and the lettering of the steroidal rings is indicated for pregnanedione and lithocholic acid. The structure to the right of lithocholic acid illustrates the most stable orientation of the A, B, and C steroid rings for 5β-bile salts (like lithocholic acid) with the A/B cis configuration (referring to the relative orientation of the hydrogen atom substituents on carbon atoms 5 and 10). The structure to the right of 5α-cyprinol sulfate shows the most stable orientation of 5α-bile salts (like 5α-cyprinol sulfate) that prefentially adopt the A/B trans configuration.
Mentions: The pregnane X receptor (PXR; NR1I2; also known as steroid and xenobiotic receptor) is a member of the nuclear hormone receptor (NR) superfamily [1,2]. PXR functions as a ligand-activated transcription factor and regulates the metabolism, transport, and excretion of exogenous compounds, steroid hormones, vitamins, bile salts, and xenobiotics. A remarkably diverse array of compounds activate human PXR, although generally only at micromolar concentrations (less commonly at high nanomolar concentrations), consistent with a hypothesized function of PXR as a toxic compound sensor [3,4] (see Figure 1 for chemical structures of some PXR activators).

Bottom Line: In addition, we compared in detail the selectivity of human and zebrafish PXRs for steroidal compounds and xenobiotics.In contrast to other nuclear hormone receptors, PXRs show significant differences in ligand specificity across species.The Western clawed frog PXR, like that described for African clawed frog PXRs, has diverged considerably in ligand selectivity from fish, bird, and mammalian PXRs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Collaborations in Chemistry, Inc., Jenkintown, PA, USA. ekinssean@yahoo.com

ABSTRACT

Background: The pregnane X receptor (PXR) shows the highest degree of cross-species sequence diversity of any of the vertebrate nuclear hormone receptors. In this study, we determined the pharmacophores for activation of human, mouse, rat, rabbit, chicken, and zebrafish PXRs, using a common set of sixteen ligands. In addition, we compared in detail the selectivity of human and zebrafish PXRs for steroidal compounds and xenobiotics. The ligand activation properties of the Western clawed frog (Xenopus tropicalis) PXR and that of a putative vitamin D receptor (VDR)/PXR cloned in this study from the chordate invertebrate sea squirt (Ciona intestinalis) were also investigated.

Results: Using a common set of ligands, human, mouse, and rat PXRs share structurally similar pharmacophores consisting of hydrophobic features and widely spaced excluded volumes indicative of large binding pockets. Zebrafish PXR has the most sterically constrained pharmacophore of the PXRs analyzed, suggesting a smaller ligand-binding pocket than the other PXRs. Chicken PXR possesses a symmetrical pharmacophore with four hydrophobes, a hydrogen bond acceptor, as well as excluded volumes. Comparison of human and zebrafish PXRs for a wide range of possible activators revealed that zebrafish PXR is activated by a subset of human PXR agonists. The Ciona VDR/PXR showed low sequence identity to vertebrate VDRs and PXRs in the ligand-binding domain and was preferentially activated by planar xenobiotics including 6-formylindolo-[3,2-b]carbazole. Lastly, the Western clawed frog (Xenopus tropicalis) PXR was insensitive to vitamins and steroidal compounds and was activated only by benzoates.

Conclusion: In contrast to other nuclear hormone receptors, PXRs show significant differences in ligand specificity across species. By pharmacophore analysis, certain PXRs share similar features such as human, mouse, and rat PXRs, suggesting overlap of function and perhaps common evolutionary forces. The Western clawed frog PXR, like that described for African clawed frog PXRs, has diverged considerably in ligand selectivity from fish, bird, and mammalian PXRs.

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Related in: MedlinePlus