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In Vitro Biotransformation of the Nrf2 Activator Bardoxolone: Formation of an Epoxide Metabolite That Undergoes Two Novel Glutathione-Mediated Metabolic Pathways: Epoxide Reduction and Oxidative Elimination of Nitrile Moiety

  • Amin M. Kamel*
    Amin M. Kamel
    Department of Global Drug Metabolism and Pharmacokinetics, Takeda, San Diego, California 92121, United States
    *Tel.: 619-930-8227. E-mail: [email protected]
  • Stephen Bowlin
    Stephen Bowlin
    Department of Global Drug Metabolism and Pharmacokinetics, Takeda, San Diego, California 92121, United States
  • Ban Anwar
    Ban Anwar
    Department of Global Drug Metabolism and Pharmacokinetics, Takeda, San Diego, California 92121, United States
    More by Ban Anwar
  • Holly Reichard
    Holly Reichard
    Department of Chemistry, Takeda, San Diego, California 92121, United States
  • Joe Argus
    Joe Argus
    Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angles, Los Angeles, California 90095, United States
    More by Joe Argus
  • , and 
  • Ian A. Blair
    Ian A. Blair
    Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6606, United States
    More by Ian A. Blair
Cite this: Chem. Res. Toxicol. 2019, 32, 11, 2268–2280
Publication Date (Web):October 15, 2019
https://doi.org/10.1021/acs.chemrestox.9b00289
Copyright © 2019 American Chemical Society

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    Abstract

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    Metabolism of bardoxolone methyl (BARD-Me), an oleanolic acid derivative, and its epoxide metabolite was studied in different in vitro systems. BARD-Me also undergoes glutathione (GSH)-adduct formation via direct nucleophilic attack at the β-carbon of the α,β-unsaturated ketone substituent on the A-ring. The presence of an electron-withdrawing nitrile residue on the α-carbon increases the α,β-unsaturated ketone’s susceptibility to nucleophilic attack by thiols. This allows BARD-Me to generate reversible adducts with the thiol groups of cysteine residues in target proteins without the potential toxic liabilities of irreversible covalent adduct formation. However, BARD-Me epoxide can also react with thiols irreversibly. Therefore, the epoxide was synthesized and its metabolic fate studied in vitro. BARD-Me epoxide was found to undergo two novel metabolic biotransformations: epoxide reduction and oxidative elimination of nitrile moiety. Both metabolic pathways proceed via nucleophilic attack of the thiol group of GSH at each of the two carbon atoms of the epoxide as evidenced by the formation of two β-hydroxy sulfide regioisomers. Oxidative elimination of nitrile moiety proceeds via nucleophilic attack of the thiol group of GSH at the epoxide carbon atom that is β to the cyano group to give a cyanohydrin metabolite, which spontaneously decomposes to release cyanide and the corresponding ketone. Nucleophilic attack of the thiol group of GSH at the epoxide carbon atom that is α to the cyano group results in the formation of the GSH monoadduct that undergoes intermolecular reduction with another GSH molecule, followed by elimination of oxidized GSH (GS-SG) and the formation of an enolate intermediate. Upon protonation, the enolate intermediate gives rise to hydroxylated BARD-Me, which is readily converted back to BARD-Me through the elimination of water. The chemical reactivity of the epoxide metabolite and the liberation of cyanide are of significant toxicological interest for the potential utility of BARD-Me as a therapeutic agent.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrestox.9b00289.

    • Collision-induced dissociation (CID) mass spectra of [M + H]+ of M1 of BARD-Me and BARD-Me epoxide and 1H NMR spectra of BARD-Me and BARD-Me epoxide (PDF)

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    Cited By

    This article is cited by 6 publications.

    1. Tonibelle Gatbonton-Schwager, Yoko Yagishita, Tanvi Joshi, Nobunao Wakabayashi, Harini Srinivasan, Takafumi Suzuki, Masayuki Yamamoto, Thomas W. Kensler. A Point Mutation at C151 of Keap1 of Mice Abrogates NRF2 Signaling, Cytoprotection in Vitro, and Hepatoprotection in Vivo by Bardoxolone Methyl (CDDO-Me). Molecular Pharmacology 2023, 104 (2) , 51-61. https://doi.org/10.1124/molpharm.123.000671
    2. Oksana V. Salomatina, Aleksandra V. Sen’kova, Arseny D. Moralev, Innokenty A. Savin, Nina I. Komarova, Nariman F. Salakhutdinov, Marina A. Zenkova, Andrey V. Markov. Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo. International Journal of Molecular Sciences 2022, 23 (11) , 6214. https://doi.org/10.3390/ijms23116214
    3. Dan Wang, Cheng Wang, Xueqin Hao, Gabriela Carter, Rafaela Carter, William J. Welch, Christopher S. Wilcox. Activation of Nrf2 in Mice Causes Early Microvascular Cyclooxygenase-Dependent Oxidative Stress and Enhanced Contractility. Antioxidants 2022, 11 (5) , 845. https://doi.org/10.3390/antiox11050845
    4. Oya Unsal Tan, Merve Zengin. Insights into the chemistry and therapeutic potential of acrylonitrile derivatives. Archiv der Pharmazie 2022, 355 (3) https://doi.org/10.1002/ardp.202100383
    5. Jianhua Li, Yayun Zhang, Weikun Meng, Guanyong Su. First insight on in vitro metabolism of three newly identified aryl organophosphate esters via a suspect coupled with nontarget screening approach. Toxicology Letters 2021, 348 , 73-84. https://doi.org/10.1016/j.toxlet.2021.05.009
    6. Zhiying Pang, Zengxin Jiang, Runwen Zhu, Chunfeng Song, Han Tang, Lu Cao, Changan Guo. Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in vitro and Alleviates Osteoarthritis in vivo. Drug Design, Development and Therapy 2021, Volume 15 , 3735-3747. https://doi.org/10.2147/DDDT.S314767

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