Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F18%3A10383090" target="_blank" >RIV/00216208:11150/18:10383090 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11160/18:10383090 RIV/61989592:15110/18:73590745 RIV/00179906:_____/18:10383090

Result on the web

<a href="http://www.frontiersin.org/articles/10.3389/fphar.2018.00993/full" target="_blank" >http://www.frontiersin.org/articles/10.3389/fphar.2018.00993/full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3389/fphar.2018.00993" target="_blank" >10.3389/fphar.2018.00993</a>

Result language

angličtina

Original language name

Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

Original language description

The constitutive androstane receptor (CAR) is a nuclear receptor involved mainly in xenobiotic and endobiotic metabolism regulation. CAR is activated directly by its ligands via the ligand binding domain (LBD) or indirectly by inhibition of the epidermal growth factor (EGF) signaling. We found that leflunomide (LEF) and its main metabolite teriflunomide (TER), both used for autoimmune diseases treatment, induce the prototype CAR target gene CYP2B6 in primary human hepatocytes. As TER was discovered to be an EGF receptor antagonist, we sought to determine if TER is an indirect activator of CAR. In primary human hepatocytes and in differentiated HepaRG cells, we found that LEF and TER up-regulate CAR target genes CYP2B6 and CYP3A4 mRNAs and enzymatic activities. TER stimulated CAR+A mutant translocation into the nucleus but neither LEF nor TER activated the CAR LBD, CAR3 variant or pregnane X receptor (PXR) in gene reporter assays. Interestingly, TER significantly up-regulated CAR mRNA expression, a result which could be a consequence of both EGF receptor and ELK-1 transcription factor inhibition by TER or by TER-mediated activation of glucocorticoid receptor (GR), an upstream hormonal regulator of CAR. We can conclude that TER is a novel indirect CAR activator which through EGF inhibition and GR activation controls both detoxification and some intermediary metabolism genes.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30104 - Pharmacology and pharmacy

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

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

Publication year

2018

Confidentiality

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

Name of the periodical

Frontiers in Pharmacology

ISSN

1663-9812

e-ISSN

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Volume of the periodical

9

Issue of the periodical within the volume

October

Country of publishing house

CH - SWITZERLAND

Number of pages

14

Pages from-to

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UT code for WoS article

000447015700001

EID of the result in the Scopus database

2-s2.0-85055352393