Bioactivation of Quinolines in a Recombinant Estrogen Receptor Transactivation Assay Is Catalyzed by N-Methyltransferases
Date
2019
Authors
Brinkmann, Markus
Barz, Bogdan
Carrière, Danielle
Velki, Mirna
Smith, Kilian
Meyer-Alert, Henriette
Müller, Yvonne
Thalmann, Beat
Bluhm, Kersti
Schiwy, Sabrina
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ACS Publications
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Article
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Abstract
Hydroxylation 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.
Description
This 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.
Keywords
ERα CALUX, estrogenicity, hetero-PAHs, NSO-PAC, Methylation, Aldehyde oxidase
Citation
Chem. Res. Toxicol. 2019, 32, 4, 698–707 Publication Date:March 21, 2019 https://doi.org/10.1021/acs.chemrestox.8b00372
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Citation
Chem. Res. Toxicol. 2019, 32, 4, 698–707 Publication Date:March 21, 2019 https://doi.org/10.1021/acs.chemrestox.8b00372
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DOI
10.1021/acs.chemrestox.8b00372
10.1021/acs.chemrestox.8b00372
10.1021/acs.chemrestox.8b00372