Synergistically enhanced CYP2B6 inducibility between a polymorphic mutation in CYP2B6 promoter and pregnane X receptor activation.

Molecular Pharmacology
Haishan LiHongbing Wang

Abstract

CYP2B6 is a highly inducible and polymorphic enzyme involved in the metabolism of an increasing number of clinically important drugs. Significant interindividual variability in CYP2B6 expression has been attributed to either genetic polymorphisms or chemical-mediated induction through the activation of constitutive androstane receptor and/or pregnane X receptor (PXR). It was reported that the -82T→C substitution within the CYP2B6*22 allele creates a functional CCAAT/enhancer-binding protein (C/EBP) binding site and enhances the basal expression of the CYP2B6 gene. Here, we explored whether this polymorphic mutation could affect drug-mediated induction of CYP2B6. Cell-based promoter reporter assays demonstrated that CYP2B6 luciferase activity was synergistically enhanced in the presence of both -82T→C mutation and rifampicin (RIF)-activated PXR. On the other hand, this synergism was attenuated by disrupting the C/EBP binding site or knocking down C/EBPα expression. Mechanistic studies revealed that C/EBPα plays an important role in such synergism by directly interacting with PXR; enhancing RIF-mediated recruitment of PXR to the -82T→C harboring CYP2B6 promoter; and looping the PXR-bound distal phenobarbital-responsive enhancer m...Continue Reading

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Citations

Oct 7, 2016·Acta Pharmaceutica Sinica. B·William D HedrichHongbing Wang
Nov 16, 2012·Drug Metabolism and Drug Interactions·Miia Turpeinen, Ulrich M Zanger
Jan 16, 2021·Clinical Pharmacology and Therapeutics·Zeruesenay DestaAndrea Gaedigk
Aug 24, 2010·Advanced Drug Delivery Reviews·Antonia H Tolson, Hongbing Wang

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