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In-line formation and identification of toxic reductive metabolites of aristolochic acid using electrochemistry mass spectrometry coupling

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Abstract

Small-molecule metabolism has been extensively studied in the past decades, notably driven by the development of new pharmaceutical ingredients. The understanding of metabolism is critical to the anticipation of reactive metabolite formation in vivo that is often associated with toxicity. Electrochemistry has been proposed to simulate the oxidoreductive metabolism reaction catalyzed by cytochrome P450, a family of microsomal enzymes strongly involved in xenobiotic metabolism. The implementation of an electrochemical cell online with mass spectrometry allows for the fast formation and identification of the reaction end products. This study discusses the ability of the synthetic electrochemical approach to simulate a complex lactamization reaction that involves the formation of reactive metabolites. Aristolochic acid I was used as a model molecule to evaluate the ability of electrochemical simulation to generate nitroso, hydroxylamine, N-hydroxylactam, lactam, and nitrenium ion metabolites.

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Authors and Affiliations

  1. Michigan State University, Department of Fisheries and Wildlife, 293 Farm Lane East, Lansing, MI, 22101, USA

    Ugo Bussy

  2. Université de Nantes, CNRS, CEISAM UMR 6230, 44000, Nantes, France

    Renaud Boisseau, Ranil C. T. Temgoua & Mohammed Boujtita

  3. Université de Nantes, CHU Nantes, CNRS, INSERM, l’institut du thorax, 44000, Nantes, France

    Mikaël Croyal

  4. Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, 44000, Nantes, France

    Mikaël Croyal

  5. CRNH-Ouest Mass Spectrometry Core Facility, 44000, Nantes, France

    Mikaël Croyal

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  1. Ugo Bussy
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  2. Renaud Boisseau
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  3. Mikaël Croyal
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  4. Ranil C. T. Temgoua
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  5. Mohammed Boujtita
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Contributions

UB conceptualized the research, contributed to the data interpretation, and drafted the manuscript. RB ran the experiments, contributed to the conceptualization of research, interpreted the data, and contributed to manuscript writing. MC contributed to experiment and data interpretation. RT contributed to manuscript writing. MB contributed to research conceptualization, supervised research, and contributed to writing.

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UB is currently employed by Mars Incorporated. All the other authors declare no competing interests.

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Bussy, U., Boisseau, R., Croyal, M. et al. In-line formation and identification of toxic reductive metabolites of aristolochic acid using electrochemistry mass spectrometry coupling. Anal Bioanal Chem 414, 2363–2370 (2022). https://doi.org/10.1007/s00216-022-03874-2

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  • DOI: https://doi.org/10.1007/s00216-022-03874-2

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