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Aldehyde oxidase mediated enantioselective metabolic health risk of dinotefuran

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Abstract

Chiral pollutants often pose significant differential environmental health risks. In this study, the biotransformation of chiral dinotefuran (DIN) and its enantioselective metabolic toxicity mechanisms have been systemically investigated. Firstly, reversed-phase chromatography-high resolution mass spectrometry was developed to quantify the content of DIN R/S chiral enantiomer with pg level sensitivity, revealing a lower elimination rate constant (Ke) of S-DIN (0.730 h−1) than R-DIN (0.746 h−1). Secondly, the interaction mechanism between DIN metabolism and important endogenous bioactive molecules, such as aldehyde oxidase (AOX) and neurotransmitters, was revealed. The DIN nitro-group was converted into a guanidine group by the reducing site of nearby flavin adenine dinucleotide (FAD) in AOX with the preferred higher affinity of S-configuration. Meanwhile, the endogenous tryptophan (Trp) aldehyde metabolic intermediate, 5-hydroxyindoleacetaldehyde (5-HIAL), provides a persistent electron donor for DIN reduction via the oxidation-catalyzed site in AOX, resulting in remarkable up-regulation of monoamine neurotransmitters such as serotonin and dopamine. Thirdly, the higher level of neurotransmitters further mediated dysregulation of oxylipin homeostasis via the serotonergic pathway, where S-DIN exhibited more pronounced liver lipid damage and environmental health risk with the accumulated lipid biomarkers, oxidized triglyceride (OxTG) and oxidized sphingomyelin (OxSM). This study elucidates the AOX-mediated enantioselectivity metabolic pathway of DIN, providing a new analytical method for chiral pollutants and paves the way for their health risk assessments.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (22276076, 22306074, 22361132536, 22236002), and the Fundamental Research Funds for the Central Universities (JUSRP622032), and the Jiangsu Association for Science and Technology Youth Science and Technology Talent Support Project (TJ-2021-049).

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Authors and Affiliations

  1. State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, China

    Liwei Xu, Xinxin Xu, Hua Kuang, Chuanlai Xu & Xiaoling Wu

  2. International Joint Research Laboratory for Biointerface and Biodetection and School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China

    Liwei Xu, Xinxin Xu, Hua Kuang, Chuanlai Xu & Xiaoling Wu

  3. Collaborative Innovation center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, 214122, China

    Liwei Xu, Xinxin Xu, Hua Kuang, Chuanlai Xu & Xiaoling Wu

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  1. Liwei Xu
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Correspondence to Xiaoling Wu.

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Supporting information The supporting information is available online at chem.scichina.com and link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Xu, L., Xu, X., Kuang, H. et al. Aldehyde oxidase mediated enantioselective metabolic health risk of dinotefuran. Sci. China Chem. (2024). https://doi.org/10.1007/s11426-023-2007-9

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