The pregnane X receptor down-regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for ("squelching") SRC-1 coactivator

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F16%3A10328924" target="_blank" >RIV/00216208:11160/16:10328924 - isvavai.cz</a>

Result on the web

<a href="http://onlinelibrary.wiley.com/doi/10.1111/bph.13472/full" target="_blank" >http://onlinelibrary.wiley.com/doi/10.1111/bph.13472/full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/bph.13472" target="_blank" >10.1111/bph.13472</a>

Result language

angličtina

Original language name

The pregnane X receptor down-regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for ("squelching") SRC-1 coactivator

Original language description

Background and Purpose The organic cation transporter 1 (OCT1) transports cationic drugs into hepatocytes. The high hepatic expression of OCT1 is controlled by the HNF4alpha and USF transcription factors. Pregnane X receptor (PXR) mediates induction of the principal xenobiotic metabolizing enzymes and transporters in the liver. Here, we have assessed the down-regulation of OCT1 expression by PXR activation. Experimental Approach We used primary human hepatocytes and related cell lines to measure OCT1 expression and activity, by assaying MPP+ accumulation. Western blotting, qRT-PCR, the OCT1 promoter gene reporter constructs and chromatin immunoprecipitation assays were also used. Key Results OCT1 mRNA in human hepatocytes was down-regulated along with reduced [3H]MPP+ accumulation in differentiated HepaRG cells after treatment with rifampicin. Rifampicin and hyperforin as well as the constitutively active PXR mutant T248D suppressed activity of the 1.8kb OCT1 promoter construct in gene reporter assays. Silencing of both PXR and HNF4alpha in HepaRG cells blocked the PXR ligand-mediated down-regulation of OCT1 expression. The mutation of HNF4alpha and USF1 (E-box) responsive elements reversed the PXR-mediated inhibition in gene reporter assays. Chromatin immunoprecipitation assays indicated that PXR activation sequestrates the SRC-1 coactivator from the HNF4alpha response element and E-box of the OCT1 promoter. Consistent with these findings, exogenous overexpression of the SRC-1, but not the PGC1alpha coactivator, relieved the PXR-mediated repression of OCT1 transactivation. Conclusions and Implications PXR ligands reduced the HNF4alpha-mediated and USF-mediated transactivation of OCT1 gene expression by competing for SRC-1 and decreased delivery of a model OCT1 substrate into hepatocytes.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

FR - Pharmacology and apothecary chemistry

OECD FORD branch

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Project

<a href="/en/project/GBP303%2F12%2FG163" target="_blank" >GBP303/12/G163: Centre of drug-dietary supplements interactions and nutrigenetics</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

British Journal of Pharmacology

ISSN

0007-1188

e-ISSN

—

Volume of the periodical

173

Issue of the periodical within the volume

10

Country of publishing house

GB - UNITED KINGDOM

Number of pages

13

Pages from-to

1703-1715

UT code for WoS article

000374976000012

EID of the result in the Scopus database

2-s2.0-84962631812