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Molecular Pharmacology

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Research ArticleArticle

Mechanistic Insights of Phenobarbital-mediated activation of Human but not Mouse Pregnane X Receptor

Linhao Li, Matthew Welch, Zhihui Li, Bryan Mackowiak, Scott Heyward, Peter W Swaan and Hongbing Wang
Molecular Pharmacology July 10, 2019, mol.119.116616; DOI: https://doi.org/10.1124/mol.119.116616
Linhao Li
1 University of Maryland School of Pharmacy;
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Matthew Welch
1 University of Maryland School of Pharmacy;
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Zhihui Li
1 University of Maryland School of Pharmacy;
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Bryan Mackowiak
1 University of Maryland School of Pharmacy;
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Scott Heyward
2 Bioreclemation IVT
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Peter W Swaan
1 University of Maryland School of Pharmacy;
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Hongbing Wang
1 University of Maryland School of Pharmacy;
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Abstract

Phenobarbital (PB), a broadly used anti-seizure drug, was the first to be characterized as an inducer of cytochrome P450 (CYP) by activation of the constitutive androstane receptor (CAR). Although PB is recognized as a conserved CAR activator among species via a well-documented indirect activation mechanism, conflicting results have been reported regarding PB regulation of the pregnane X receptor (PXR), a sister receptor of CAR, and the underlying mechanisms remain elusive. Here, we show that in a human CAR-knockout (KO) HepaRG cell line, PB significantly induces the expression of CYP2B6 and CYP3A4, two shared target genes of human CAR and PXR (hCAR, hPXR). In human primary hepatocytes and hCAR-KO HepaRG cells, PB-induced expression of CYP3A4 was markedly repressed by genetic knockdown or pharmacological inhibition of hPXR. Mechanistically, PB concentration-dependently activates hPXR but not its mouse counterpart in cell-based luciferase assays. Mammalian two-hybrid assays demonstrated that PB selectively increases the functional interaction between the steroid receptor coactivator-1 and hPXR but not mouse PXR. Moreover, surface plasmon resonance binding affinity assay showed that PB directly binds to the ligand binding domain of hPXR (KD = 1.42E-05). Structure-activity analysis further revealed that the amino acid tryptophan-299 within the ligand binding pocket of hPXR plays a key role in the agonistic binding of PB and mutation of tryptophan-299 disrupts PB activation of hPXR. Collectively, these data reveal that PB, a selective mouse CAR activator, activates both hCAR and hPXR, and provide novel mechanistic insights for PB-mediated activation of hPXR.

SIGNIFICANCE STATEMENT Phenobarbital, a selective mouse CAR activator, activates both human CAR and human PXR, which may contribute to its species-specific roles in energy homeostasis and cell proliferation.

  • Cytochrome P450 (CYP)
  • Drug metabolism
  • Gene regulation
  • Pregnane X receptor (PXR)
  • Species differences
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (2)
Molecular Pharmacology
Vol. 103, Issue 2
1 Feb 2023
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Research ArticleArticle

Mechanistic Insights of Phenobarbital-mediated activation of Human but not Mouse Pregnane X Receptor

Linhao Li, Matthew Welch, Zhihui Li, Bryan Mackowiak, Scott Heyward, Peter W Swaan and Hongbing Wang
Molecular Pharmacology July 10, 2019, mol.119.116616; DOI: https://doi.org/10.1124/mol.119.116616

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Research ArticleArticle

Mechanistic Insights of Phenobarbital-mediated activation of Human but not Mouse Pregnane X Receptor

Linhao Li, Matthew Welch, Zhihui Li, Bryan Mackowiak, Scott Heyward, Peter W Swaan and Hongbing Wang
Molecular Pharmacology July 10, 2019, mol.119.116616; DOI: https://doi.org/10.1124/mol.119.116616
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