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Published on: November 15, 2013
Humanized xenobiotic response in mice expressing nuclear receptor SXR
1Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Nature
|August 10, 2000
Summary
The pregnenolone X receptor (PXR) and steroid xenobiotic receptor (SXR) are identified as key species-specific sensors. These receptors mediate the liver
Area of Science:
- Pharmacology
- Molecular Biology
- Toxicology
Background:
- Cytochrome P450 3A (CYP3A) enzymes are crucial for metabolizing drugs and endogenous compounds in the liver.
- CYP3A induction by various substrates underlies significant drug-drug interactions.
- Species-specific differences in CYP3A induction suggest involvement of cellular factors or xeno-sensors.
Purpose of the Study:
- To identify the nuclear receptor responsible for species-specific CYP3A induction.
- To elucidate the role of this receptor in xenobiotic metabolism and protection.
- To develop 'humanized' models for studying drug responses.
Main Methods:
- Gene targeting (PXR knockout mice).
- Transgenic mouse models expressing activated steroid xenobiotic receptor (SXR).
- Analysis of CYP3A gene expression and response to inducers.
Main Results:
- Targeted disruption of mouse PXR abolished CYP3A induction by known agents.
- Activated human SXR in transgenic mice led to constitutive CYP3A upregulation and enhanced xenobiotic protection.
- Receptor species origin, not CYP3A gene promoter, determined inducibility specificity.
- Humanized mice responded to human-specific inducers like rifampicin.
Conclusions:
- Steroid xenobiotic receptor (SXR) and pregnenolone X receptor (PXR) are the primary species-specific xeno-sensors.
- SXR/PXR mediate adaptive hepatic responses and xenobiotic protection.
- SXR/PXR represent a critical mechanism for human xenoprotection and drug interaction studies.
