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PXR, CAR and drug metabolism
Timothy M Willson1, Steven A Kliewer
1GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA. tmw20653@gsk.com
Abstract:
Mechanisms that protect the body from a diverse array of harmful chemicals are also involved in drug metabolism, and can cause adverse drug-drug interactions. Two closely related orphan nuclear hormone receptors--the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR)--have recently emerged as transcriptional regulators of cytochrome P450 expression that couple xenobiotic exposure to oxidative metabolism. In this review, we provide an examination of the roles of PXR and CAR as xenobiotic sensors, and discuss the application of this knowledge to toxicological screening in drug discovery.
Insights
The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate drug metabolism and can cause interactions. Understanding their roles as sensors aids toxicological screening in drug discovery.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Drug metabolism involves mechanisms protecting against harmful chemicals, which can lead to adverse drug-drug interactions.
- Orphan nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), are key regulators of drug metabolism.
- These receptors link exposure to foreign compounds (xenobiotics) with metabolic processes.
Purpose of the Study:
- To examine the roles of PXR and CAR as sensors of xenobiotics.
- To discuss the application of PXR and CAR knowledge in toxicological screening for drug discovery.
Main Methods:
- Review of existing literature on PXR and CAR.
- Analysis of the regulatory functions of PXR and CAR in cytochrome P450 expression.
- Exploration of PXR and CAR involvement in xenobiotic metabolism and drug interactions.
Main Results:
- PXR and CAR are identified as critical transcriptional regulators of cytochrome P450 enzymes.
- These receptors play a central role in mediating the body's response to xenobiotic exposure.
- Dysregulation of PXR and CAR can contribute to adverse drug-drug interactions.
Conclusions:
- PXR and CAR function as crucial sensors for xenobiotics, influencing drug metabolism.
- Knowledge of PXR and CAR mechanisms is valuable for improving toxicological screening in drug development.
- Targeting PXR and CAR pathways may offer strategies to mitigate adverse drug reactions.