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Updated: Oct 1, 2026

Real Time Monitoring of Intracellular Bile Acid Dynamics Using a Genetically Encoded FRET-based Bile Acid Sensor
09:21

Real Time Monitoring of Intracellular Bile Acid Dynamics Using a Genetically Encoded FRET-based Bile Acid Sensor

Published on: January 4, 2016

Cholesterol and bile acids regulate xenosensor signaling in drug-mediated induction of cytochromes P450

Christoph Handschin1, Michael Podvinec, Remo Amherd

  • 1Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.

The Journal of Biological Chemistry
|June 5, 2002
PubMed

Insights

Endogenous cholesterol and bile acids modulate drug-activated cytochrome P450 (CYP) enzymes. Nuclear receptors controlling lipid homeostasis and drug metabolism reveal complex interactions.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Cytochromes P450 (CYP) are crucial for xenobiotic metabolism.
  • Drug-sensing nuclear receptors like pregnane X receptor (PXR), constitutive androstane receptor (CAR), and chicken xenobiotic receptor (CXR) regulate CYP transcription.
  • Endogenous molecules such as cholesterol and bile acids can influence xenobiotic metabolism.

Purpose of the Study:

  • To investigate how endogenous cholesterol and bile acids modulate the transcriptional activation of drug-metabolizing CYPs by nuclear receptors.
  • To elucidate the competitive interactions between cholesterol-sensing receptors and drug-sensing receptors in regulating CYP gene expression.

Main Methods:

  • The study utilized reporter assays to assess transcriptional activation of CYP genes.
  • Investigated the effects of bile acids, oxysterols, and nuclear receptor activation on CYP enhancers.
  • Examined competitive binding and regulatory interactions between liver X receptor (LXR) and PXR/CAR/CXR.

Main Results:

  • Bile acids induce the chicken CYP2H1 gene via CXR.
  • Hydroxylated bile acids and oxysterols inhibit drug-induced CYP activation.
  • The cholesterol-sensing LXR competes with CXR, PXR, and CAR for regulatory control over drug-responsive enhancers of CYP genes (CYP2H1, CYP3A4, CYP2B6).

Conclusions:

  • Endogenous cholesterol and bile acids play a significant role in modulating drug metabolism by influencing CYP-regulating nuclear receptors.
  • These findings highlight a complex interplay between lipid homeostasis and xenobiotic metabolism pathways.
  • The study reveals novel insights into the regulatory network governing both lipid metabolism and drug detoxification.

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