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Acebutolol and alprenolol metabolism predictions: comparative study of electrochemical and cytochrome P450-catalyzed reactions using liquid chromatography coupled to high-resolution mass spectrometry

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Abstract

A comparative study of the electrochemical conversion and the biotransformation performed by the cytochrome P450 (CYP450) obtained by rat liver microsomes has been achieved to elucidate the oxidation mechanism of both acebutolol and alprenolol. For this purpose, a wide range of reactions such as N-dealkylation, O-dealkoxylation, aromatic hydroxylation, benzyl hydroxylation, alkyl hydroxylation, and aromatic hydroxylation have been examined in this study, and their mechanisms have been compared. Most of the results of the electrochemical oxidation have been found to be in accordance with those obtained by incubating acebutolol and alprenolol in the presence of CYP450, i.e., N-dealkylation, benzyl hydroxylation, and O-dealkoxylation reactions catalyzed by liver microsomes were found to be predicted by the electrochemical oxidation. The difficulty for the electrochemical process to mimic both aromatic and alkyl hydroxylation reactions has also been discussed, and the hypothesis for the absence of aromatic hydroxylated and alkyl hydroxylated products, respectively, for alprenolol and acebutolol, under the anodic oxidation has been supported by theoretical calculation. The present study highlights the potential and limitation of coupling of electrochemistry–liquid chromatography–high-resolution mass spectrometry for the study of phase I and phase II reactions of acebutolol and alprenolol.

The electrochemical conversion versus the biotransformation catalyzed by CYP450

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Acknowledgments

The authors thank CNRS, the University of Nantes, and the French Ministry of Higher Education and Research for financial support. D.J. acknowledges the European Research Council (ERC) and the Région des Pays de la Loire for financial support in the framework of a Starting Grant (Marches–278845) and a recrutement sur poste stratégique, respectively. This research used resources of (1) the GENCI-CINES/IDRIS (grant c2012085117), (2) Centre de Calcul Intensif des Pays de Loire (CCIPL), and (3) a local Troy cluster.

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Authors and Affiliations

  1. LUNAM Université de Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse et Modélisation (CEISAM), UMR 6230, 2 rue de la Houssinière, BP 92208, 44322, Nantes cedex 3, France

    Ugo Bussy, Chaimaâ El-Bekkali, Illa Tea, Nicolas Galland, Denis Jacquemin & Mohammed Boujtita

  2. CEA, Bioenergetics, Structural Biology and Mechanisms Unit, CNRS UMR 8221, DSV/iBiTecS, 91191, Gif-Sur-Yvette Cedex, France

    Marcel Delaforge

  3. Université de Nantes, Human Nutrition Research Center of Nantes, Plateforme Spectrométrie de Masse, IRS-UN, 8 Quai Moncousu, 44000, Nantes, France

    Véronique Ferchaud-Roucher & Michel Krempf

  4. Institut Universitaire de France, 103, Boulevard Saint-Michel, 75005, Paris Cedex 5, France

    Denis Jacquemin

Authors
  1. Ugo Bussy
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  2. Marcel Delaforge
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  3. Chaimaâ El-Bekkali
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  4. Véronique Ferchaud-Roucher
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  5. Michel Krempf
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  6. Illa Tea
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  7. Nicolas Galland
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  8. Denis Jacquemin
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  9. Mohammed Boujtita
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Correspondence to Mohammed Boujtita.

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Bussy, U., Delaforge, M., El-Bekkali, C. et al. Acebutolol and alprenolol metabolism predictions: comparative study of electrochemical and cytochrome P450-catalyzed reactions using liquid chromatography coupled to high-resolution mass spectrometry. Anal Bioanal Chem 405, 6077–6085 (2013). https://doi.org/10.1007/s00216-013-7050-7

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