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Constitutive Androstane Receptor contributes towards increased drug clearance in cholestasis

Constitutive Androstane Receptor contributes towards increased drug clearance in cholestasis

Authors :
Auinash Kalsotra
Megan E. Patton
Rahiman Faiyaz
Waqar Arif
Sayeepriyadarshini Anakk
Antony M. Wheatley
Bhoomika Mathur
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.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....441a0e7e74e0611df0766b4bc820ba63
Full Text :
https://doi.org/10.1101/520692