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

  • Author / Creator
    Aljuhani, Naif Saad
  • 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.

  • Subjects / Keywords
  • Graduation date
    2013-06
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3899V
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Siraki, Arno (Faculty of Pharmacy and Pharmaceutical Science)
  • Examining committee members and their departments
    • Siraki, Arno (Faculty of Pharmacy and Pharmaceutical Science)
    • Klotz, Lars-Oliver (Faculty of Pharmacy and Pharmaceutical Science)
    • El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Science)
    • Jonathan, Martin (Faculty of Medicine and Dentistry)
    • 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)