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Constitutive Androstane Receptor contributes towards increased drug clearance in cholestasis
Constitutive Androstane Receptor contributes towards increased drug clearance in cholestasis
- Publication Year :
- 2019
- Publisher :
- Cold Spring Harbor Laboratory, 2019.
-
Abstract
- Understanding the alterations in drug metabolism in different liver diseases is crucial for appropriate therapeutic intervention. We performed high-throughput RNA sequencing on various liver injury models, including cholestasis, diet-induced steatosis, and regeneration. Comparative liver transcriptome analysis revealed overlapping and distinct gene profiles among different liver diseases. Particularly, cholestatic livers displayed robust induction of drug metabolizing genes. This upregulation is not a generic hepatic stress response, as it was suppressed or unchanged in other models of liver diseases. Consistently, drug metabolic gene profiles were induced in a subset of biliary atresia patients, but not in individuals with hepatitis B or C viral infection, and alcoholic hepatitis. Further analysis revealed this induction was specific to genes regulated by nuclear receptor CAR (Constitutive Androstane Receptor). To test this, we challenged cholestatic mice with a paralytic agent, zoxazolamine. Compared to controls, these mice displayed significantly reduced paralysis time, reflecting increased drug metabolism, and this effect was lost upon inhibition of CAR. Thus, CAR activation can alter therapeutic efficacy of certain drugs in a subset of cholestatic individuals.
- Subjects :
- Liver injury
0303 health sciences
business.industry
Alcoholic hepatitis
Pharmacology
medicine.disease
3. Good health
03 medical and health sciences
0302 clinical medicine
Cholestasis
Nuclear receptor
Constitutive androstane receptor
medicine
030211 gastroenterology & hepatology
Zoxazolamine
Steatosis
business
Drug metabolism
030304 developmental biology
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....441a0e7e74e0611df0766b4bc820ba63
- Full Text :
- https://doi.org/10.1101/520692