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Bioactivation of Quinolines in a Recombinant Estrogen Receptor Transactivation Assay Is Catalyzed by N-Methyltransferases

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dc.contributor.authorBrinkmann, Markus
dc.contributor.authorBarz, Bogdan
dc.contributor.authorCarrière, Danielle
dc.contributor.authorVelki, Mirna
dc.contributor.authorSmith, Kilian
dc.contributor.authorMeyer-Alert, Henriette
dc.contributor.authorMüller, Yvonne
dc.contributor.authorThalmann, Beat
dc.contributor.authorBluhm, Kersti
dc.contributor.authorSchiwy, Sabrina
dc.contributor.authorHotz, Simone
dc.contributor.authorSalowsky, Helena
dc.contributor.authorTiehm, Andreas
dc.contributor.authorHecker, Markus
dc.contributor.authorHollert, Henner
dc.date.accessioned2023-10-18T15:12:18Z
dc.date.available2023-10-18T15:12:18Z
dc.date.issued2019
dc.descriptionThis document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Chemical Research in Toxicology, copyright © 2019 American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/acs.chemrestox.8b00372.en_US
dc.description.abstractHydroxylation of polyaromatic compounds through cytochromes P450 (CYPs) is known to result in potentially estrogenic transformation products. Recently, there has been an increasing awareness of the importance of alternative pathways such as aldehyde oxidases (AOX) or N-methyltransferases (NMT) in bioactivation of small molecules, particularly N-heterocycles. Therefore, this study investigated the biotransformation and activity of methylated quinolines, a class of environmentally relevant N-heterocycles that are no native ligands of the estrogen receptor (ER), in the estrogen-responsive cell line ERα CALUX. We found that this widely used cell line overexpresses AOXs and NMTs while having low expression of CYP enzymes. Exposure of ERα CALUX cells to quinolines resulted in estrogenic effects, which could be mitigated using an inhibitor of AOX/NMTs. No such mitigation occurred after coexposure to a CYP1A inhibitor. A number of N-methylated but no hydroxylated transformation products were detected using liquid chromatography–mass spectrometry, which indicated that biotransformations to estrogenic metabolites were likely catalyzed by NMTs. Compared to the natural ER ligand 17β-estradiol, the products formed during the metabolization of quinolines were weak to moderate agonists of the human ERα. Our findings have potential implications for the risk assessment of these compounds and indicate that care must be taken when using in vitro estrogenicity assays, for example, ERα CALUX, for the characterization of N-heterocycles or environmental samples that may contain them.en_US
dc.description.sponsorshipGerman soil and water conservation boards (LABO/LAWA) and the SOLUTIONS project (funded by the European Union Seventh Framework Programme under grant agreement number 603437)en_US
dc.description.versionPeer Revieweden_US
dc.identifier.citationChem. Res. Toxicol. 2019, 32, 4, 698–707 Publication Date:March 21, 2019 https://doi.org/10.1021/acs.chemrestox.8b00372en_US
dc.identifier.doi10.1021/acs.chemrestox.8b00372
dc.identifier.doi10.1021/acs.chemrestox.8b00372
dc.identifier.urihttps://hdl.handle.net/10388/15145
dc.language.isoenen_US
dc.publisherACS Publicationsen_US
dc.subjectERα CALUXen_US
dc.subjectestrogenicityen_US
dc.subjecthetero-PAHsen_US
dc.subjectNSO-PACen_US
dc.subjectMethylationen_US
dc.subjectAldehyde oxidaseen_US
dc.titleBioactivation of Quinolines in a Recombinant Estrogen Receptor Transactivation Assay Is Catalyzed by N-Methyltransferasesen_US
dc.typeArticleen_US

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