Humanized xenobiotic response in mice expressing nuclear receptor SXR

Wen Xie, Joyce L. Barwick, Michael Downes, Bruce Blumberg, Cynthia M. Simon, Michael C. Nelson, Brent A. Neuschwander-Tetri, Elizabeth M. Brunt, Philip S. Guzelian and Ronald M. Evans ()
Additional contact information
Wen Xie: Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies
Joyce L. Barwick: Medical Toxicology, University of Colorado Health Sciences Centre
Michael Downes: Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies
Bruce Blumberg: University of California
Cynthia M. Simon: Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies
Michael C. Nelson: Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies
Brent A. Neuschwander-Tetri: and
Elizabeth M. Brunt: St. Louis University School of Medicine
Philip S. Guzelian: Medical Toxicology, University of Colorado Health Sciences Centre
Ronald M. Evans: Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies

Nature, 2000, vol. 406, issue 6794, 435-439

Abstract: Abstract The cytochrome CYP3A gene products, expressed in mammalian liver, are essential for the metabolism of lipophilic substrates, including endogenous steroid hormones and prescription drugs1,2. CYP3A enzymes are extremely versatile and are inducible by many of their natural and xenobiotic substrates. Consequently, they form the molecular basis for many clinical drug–drug interactions3. The induction of CYP3A enzymes is species-specific4,5, and we have postulated that it involves one or more cellular factors, or receptor-like xeno-sensors6. Here we identify one such factor unequivocally as the nuclear receptor pregnenolone X receptor (PXR)7,8 and its human homologue, steroid and xenobiotic receptor (SXR)8,9,10. We show that targeted disruption of the mouse PXR gene abolishes induction of CYP3A by prototypic inducers such as dexamethasone or pregnenolone-16α-carbonitrile. In transgenic mice, an activated form of SXR causes constitutive upregulation of CYP3A gene expression and enhanced protection against toxic xenobiotic compounds. Furthermore, we show that the species origin of the receptor, rather than the promoter structure of CYP3A genes, dictates the species-specific pattern of CYP3A inducibility. Thus, we can generate ‘humanized’ transgenic mice that are responsive to human-specific inducers such as the antibiotic rifampicin. We conclude that SXR/PXR genes encode the primary species-specific xeno-sensors that mediate the adaptive hepatic response, and may represent the critical biochemical mechanism of human xenoprotection.

Date: 2000
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/35019116 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:406:y:2000:i:6794:d:10.1038_35019116

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/35019116

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().