The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.
Jürgen M. Lehmann,David D. McKee,Michael A. Watson,Timothy M. Willson,John T. Moore,Steven A. Kliewer +5 more
TLDR
The identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP 3A4 expression is reported.Abstract:
The cytochrome P-450 monooxygenase 3A4 (CYP3A4) is responsible for the oxidative metabolism of a wide variety of xenobiotics including an estimated 60% of all clinically used drugs. Although expression of the CYP3A4 gene is known to be induced in response to a variety of compounds, the mechanism underlying this induction, which represents a basis for drug interactions in patients, has remained unclear. We report the identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP3A4 expression. Comparison of hPXR with the recently cloned mouse PXR reveals marked differences in their activation by certain drugs, which may account in part for the species-specific effects of compounds on CYP3A gene expression. These findings provide a molecular explanation for the ability of disparate chemicals to induce CYP3A4 levels and, furthermore, provide a basis for developing in vitro assays to aid in predicting whether drugs will interact in humans.read more
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Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.
Peter M. Kuehl,Jiong Zhang,Yvonne S. Lin,Jatinder K. Lamba,Mahfoud Assem,John D. Schuetz,Paul B. Watkins,Ann K. Daly,Steven A. Wrighton,Stephen D. Hall,Patrick Maurel,Mary V. Relling,Cynthia Brimer,Kazuto Yasuda,Raman Venkataramanan,Stephen C. Strom,Kenneth E. Thummel,Mark S. Boguski,Erin G. Schuetz +18 more
TL;DR: CYP3A5 was more frequently expressed in livers of African Americans than in those of Caucasians, and may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.
Journal ArticleDOI
The PPARs: from orphan receptors to drug discovery.
Journal ArticleDOI
A Regulatory Cascade of the Nuclear Receptors FXR, SHP-1, and LRH-1 Represses Bile Acid Biosynthesis
Bryan Goodwin,Stacey A. Jones,Roger R. Price,Michael A. Watson,D.D. McKee,Linda B. Moore,Cristin M. Galardi,Joan G. Wilson,Michael C. Lewis,Matthew E. Roth,Patrick R. Maloney,Timothy M. Willson,Steven A. Kliewer +12 more
TL;DR: A potent, nonsteroidal FXR ligand is used to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain that provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
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The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity
Jeff L. Staudinger,Jeff L. Staudinger,Bryan Goodwin,Stacey A. Jones,Diane Hawkins-Brown,Kathleen I. MacKenzie,Anne M. Latour,Yaping Liu,Curtis D. Klaassen,Kathleen K. Brown,John F. Reinhard,Timothy M. Willson,Beverly H. Koller,Steven A. Kliewer +13 more
TL;DR: It is proposed that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid, and suggest that PxR agonists may prove useful in the treatment of human cholestatic liver disease.
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Induction of phase I, II and III drug metabolism/transport by xenobiotics
TL;DR: Drug metabolizing enzymes (DMEs) play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body, and play crucial roles in response to many polycyclic aromatic hydrocarbon receptors and excretion.
References
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