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Permanent link (DOI): https://doi.org/10.7939/R3899V

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Enhancement of menadione cytotoxicity by bicarbonate: redox cycling and a possible role for the carbonate radical in quinone cytotoxicity Open Access

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Other title
Subject/Keyword
ascorbic acid, cytotoxicity, carbonate radical
quinones, menadione, redox cycling
menadione, cytotoxicity, carbonate radical, bicarbonate, superoxide dismutase, Hepa1c1c7 cells
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Aljuhani, Naif Saad
Supervisor and department
Siraki, Arno (Faculty of Pharmacy and Pharmaceutical Science)
Examining committee member and department
El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Science)
Jonathan, Martin (Faculty of Medicine and Dentistry)
Klotz, Lars-Oliver (Faculty of Pharmacy and Pharmaceutical Science)
El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Science), Klotz, Lars-Oliver (Faculty of Pharmacy and Pharmaceutical Science), Jonathan, Martin (Faculty of Medicine and Dentistry)
Siraki, Arno (Faculty of Pharmacy and Pharmaceutical Science)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2013-01-07T09:12:58Z
Graduation date
2013-06
Degree
Master of Science
Degree level
Master's
Abstract
We investigated the effect of bicarbonate on quinone redox cycling and cytotoxicity. A cell-free system utilized menadione and ascorbic acid to catalyze a redox cycle, and we utilized murine hepatoma (Hepa 1c1c7) cells for in vitro experiments. Experiments were performed using low (2 mM) vs physiological (25 mM) bicarbonate levels in buffer equilibrated to physiological pH. We found that menadione redox cycling was enhanced by bicarbonate using oximetry and ascorbic acid oxidation. Furthermore, we treated Hepa1c1c7 cells with menadione and found that cytotoxicity and oxidative stress (dichlorofluorescin oxidation) was significantly increased with physiological bicarbonate-containing media. Interestingly, the inhibition of superoxide dismutase (SOD) showed a protective effect against menadione cytotoxicity. Using isolated BSA protein, we found a significant increase in protein carbonyls with menadione/ascorbate/SOD with physiological bicarbonate levels; low bicarbonate or SOD-omitted reactions produced less protein carbonyls. In conclusion, these findings suggest that the hydrogen peroxide generated by menadione redox cycling together with bicarbonate are substrates for SOD peroxidase activity that leads to carbonate radical which enhances cytotoxicity. These findings may represent an additional mechanism of quinone-induced toxicity.
Language
English
DOI
doi:10.7939/R3899V
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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