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The Butter Flavorant, Diacetyl, Exacerbates β-Amyloid Cytotoxicity

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Center for Drug Design, Academic Health Center, University of Minnesota, 308 Harvard Street SE, 8-123A WDH, Minneapolis, Minnesota 55455, United States
*E-mail: [email protected]
Cite this: Chem. Res. Toxicol. 2012, 25, 10, 2083–2091
Publication Date (Web):June 25, 2012
https://doi.org/10.1021/tx3001016
Copyright © 2012 American Chemical Society
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    Abstract

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    Diacetyl (DA), an ubiquitous butter-flavoring agent, was found to influence several aspects of amyloid-β (Aβ) aggregation—one of the two primary pathologies associated with Alzheimer's disease. Thioflavin T fluorescence and circular dichroism spectroscopic measurements revealed that DA accelerates Aβ1–42 aggregation into soluble and ultimately insoluble β-pleated sheet structures. DA was found to covalently bind to Arg5 of Aβ1–42 through proteolytic digestion–mass spectrometric experiments. These biophysical and chemical effects translated into the potentiation of Aβ1–42 cytotoxicity by DA toward SH-SY5Y cells in culture. DA easily traversed through a MDR1-MDCK cell monolayer, an in vitro model of the blood–brain barrier. Additionally, DA was found not only to be resistant to but also inhibitory toward glyoxalase I, the primary initiator of detoxification of amyloid-promoting reactive dicarbonyl species that are generated naturally in large amounts by neuronal tissue. In light of the chronic exposure of industry workers to DA, this study raises the troubling possibility of long-term neurological toxicity mediated by DA.

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    Figures of CD spectra, mass spectrometric analysis, and DA-induced increases in the cytotoxicity of Aβ1–42 peptide. This material is available free of charge via the Internet at http://pubs.acs.org.

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    15. Joel R. Frandsen, Prabagaran Narayanasamy. Neuroprotection through flavonoid: Enhancement of the glyoxalase pathway. Redox Biology 2018, 14 , 465-473. https://doi.org/10.1016/j.redox.2017.10.015
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    17. Lucia Marri, Anita M. Jansson, Caspar E. Christensen, Ole Hindsgaul. An enzyme-linked immunosorbent assay for the detection of diacetyl (2,3-butanedione). Analytical Biochemistry 2017, 535 , 12-18. https://doi.org/10.1016/j.ab.2017.07.021
    18. M.W. Anders. Diacetyl and related flavorant α-Diketones: Biotransformation, cellular interactions, and respiratory-tract toxicity. Toxicology 2017, 388 , 21-29. https://doi.org/10.1016/j.tox.2017.02.002
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    22. Van K. Holden, Stella E. Hines. Update on flavoring-induced lung disease. Current Opinion in Pulmonary Medicine 2016, 22 (2) , 158-164. https://doi.org/10.1097/MCP.0000000000000250
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    24. Mohamed B. Abou‐Donia, Mohamed Salama. Food Additives. 2015, 269-287. https://doi.org/10.1002/9781118683484.ch13
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    26. Timothy R. Fennell, Daniel L. Morgan, Scott L. Watson, Suraj Dhungana, Suramya Waidyanatha. Systemic uptake, albumin and hemoglobin binding of [14C]2,3-butanedione administered by intratracheal instillation in male Harlan Sprague Dawley rats and oropharyngeal aspiration in male B6C3F1/N mice. Chemico-Biological Interactions 2015, 227 , 112-119. https://doi.org/10.1016/j.cbi.2014.12.029
    27. Francine L. Kelly, Jesse Sun, Bernard M. Fischer, Judith A. Voynow, Apparao B. Kummarapurugu, Helen L. Zhang, Julia L. Nugent, Robert F. Beasley, Tereza Martinu, William M. Gwinn, Daniel L. Morgan, Scott M. Palmer. Diacetyl Induces Amphiregulin Shedding in Pulmonary Epithelial Cells and in Experimental Bronchiolitis Obliterans. American Journal of Respiratory Cell and Molecular Biology 2014, 51 (4) , 568-574. https://doi.org/10.1165/rcmb.2013-0339OC
    28. . Evaluation of a scientific publication associating diacetyl with enhancement of β‐amyloid‐induced neurotoxicity. EFSA Journal 2013https://doi.org/10.2903/j.efsa.2013.3474
    29. Eric J. Zaccone, Janet A. Thompson, Dovenia S. Ponnoth, Amy M. Cumpston, W. Travis Goldsmith, Mark C. Jackson, Michael L. Kashon, David G. Frazer, Ann F. Hubbs, Michael J. Shimko, Jeffrey S. Fedan. Popcorn Flavoring Effects on Reactivity of Rat Airways in Vivo and in Vitro. Journal of Toxicology and Environmental Health, Part A 2013, 76 (11) , 669-689. https://doi.org/10.1080/15287394.2013.796302
    30. Adele Papetti, Dora Mascherpa, Giorgio Marrubini, Gabriella Gazzani. Effect of In Vitro Digestion on Free α‐Dicarbonyl Compounds in Balsamic Vinegars. Journal of Food Science 2013, 78 (4) https://doi.org/10.1111/1750-3841.12062
    31. Ashish P Vartak, Swati S More, Robert Vince. Could the artificial butter flavoring, diacetyl, cause Alzheimer’s disease?. Neurodegenerative Disease Management 2012, 2 (6) , 557-559. https://doi.org/10.2217/nmt.12.59
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