Filling the Blank Space: Branched 4-Nonylphenol Isomers Are Responsible for Robust Constitutive Androstane Receptor (CAR) Activation by Nonylphenol

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F24%3A10479243" target="_blank" >RIV/00216208:11150/24:10479243 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11160/24:10479243

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=4dx0LoXt-o" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=4dx0LoXt-o</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.est.3c10096" target="_blank" >10.1021/acs.est.3c10096</a>

Result language

angličtina

Original language name

Filling the Blank Space: Branched 4-Nonylphenol Isomers Are Responsible for Robust Constitutive Androstane Receptor (CAR) Activation by Nonylphenol

Original language description

4-Nonylphenol (4-NP), a para-substituted phenolic compound with a straight or branched carbon chain, is a ubiquitous environmental pollutant and food contaminant. 4-NP, particularly the branched form, has been identified as an endocrine disruptor (ED) with potent activities on estrogen receptors. Constitutive Androstane Receptor (CAR) is another crucial nuclear receptor that regulates hepatic lipid, glucose, and steroid metabolism and is involved in the ED mechanism of action. An NP mixture has been described as an extremely potent activator of both human and rodent CAR. However, detailed mechanistic aspects of CAR activation by 4-NP are enigmatic, and it is not known if 4-NP can directly interact with the CAR ligand binding domain (LBD). Here, we examined interactions of individual branched (22NP, 33NP, and 353NP) and linear 4-NPs with CAR variants using molecular dynamics (MD) simulations, cellular experiments with various CAR expression constructs, recombinant CAR LBD in a TR-FRET assay, or a differentiated HepaRG hepatocyte cellular model. Our results demonstrate that branched 4-NPs display more stable poses to activate both wild-type CAR1 and CAR3 variant LBDs in MD simulations. Consistently, branched 4-NPs activated CAR3 and CAR1 LBD more efficiently than linear 4-NP. Furthermore, in HepaRG cells, we observed that all 4-NPs upregulated CYP2B6 mRNA, a relevant hallmark for CAR activation. This is the first study to provide detailed insights into the direct interaction between individual 4-NPs and human CAR-LBD, as well as its dominant variant CAR3. The work could contribute to the safer use of individual 4-NPs in many areas of industry.

Czech name

—

Czech description

—

Type

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

CEP classification

—

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

2024

Confidentiality

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

Name of the periodical

Environmental Science and Technology

ISSN

0013-936X

e-ISSN

1520-5851

Volume of the periodical

58

Issue of the periodical within the volume

16

Country of publishing house

US - UNITED STATES

Number of pages

11

Pages from-to

6913-6923

UT code for WoS article

001199628900001

EID of the result in the Scopus database

2-s2.0-85190141326