Nuclear receptor PXR: discovery of a pharmaceutical anti-target
Steven A. Kliewer
Steven A. Kliewer
Published April 1, 2015
Citation Information: J Clin Invest. 2015;125(4):1388-1389. https://doi.org/10.1172/JCI81244.
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Hindsight

Nuclear receptor PXR: discovery of a pharmaceutical anti-target

Abstract

Transcriptional induction of the gene encoding cytochrome P450 3A oxygenase (CYP3A) causes a prominent class of dangerous drug-drug interactions wherein one drug accelerates the metabolism of another. In our 1998 JCI paper, we reported the cloning of the human nuclear receptor PXR and demonstrated that it mediates CYP3A induction. We determined that PXR is expressed in liver, acts through a DNA response element located in the CYP3A promoter, and is activated by a structurally diverse collection of drugs that induce CYP3A. Our findings revealed the molecular basis for the CYP3A induction class of drug-drug interactions and provided a high-throughput means for screening out drug candidates with this activity.

Authors

Steven A. Kliewer

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Figure 1

PXR causes drug-drug interactions.

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PXR causes drug-drug interactions. Due to a large, hydrophobic ligand-bi...
Due to a large, hydrophobic ligand-binding pocket, PXR is activated by a wide variety of drugs, including dexamethasone, RU486, rifampicin, and hyperforin (a constituent of St. John’s wort). Once activated, PXR binds to the CYP3A promoter and induces transcription. Elevated levels of CYP3A result in increased metabolism of CYP3A substrates, which include most prescription drugs.