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Permanent link (DOI): https://doi.org/10.7939/R3R394

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Target Molecules for Reactive Free Radical Metabolites of Aromatic Amines Open Access

Descriptions

Other title
Subject/Keyword
Poly-unsaturated fatty acids
aromatic amine
Agranulocytosis
Myeloperoxidase
Oxidative stress
Glutathione
Idiosyncratic Drug reaction
Free radical metabolites
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
NARWALEY, MALYAJ
Supervisor and department
Siraki, G. Arno (Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences)
Martin, W. Jonathan (Medicine and Dentistry)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization

Date accepted
2011-09-28T03:47:56Z
Graduation date
2011-11
Degree
Master of Science
Degree level
Master's
Abstract
Aromatic amines during peroxidase metabolism produce N-centered cationic radicals and phenyl radicals as reactive intermediates. The latter also induce protein oxidation. These findings are associated with drug induced agranulocytosis. However, other biomolecular targets of these metabolites are unknown. We tested the reactivity of aromatic amines and congeners with selected poly-unsaturated fatty acids (PUFA) and glutathione (GSH) in the presence of horseradish peroxidase (HRP)/H2O2 by Oxygen electrode, Electron spin resonance (ESR), HPLC and immunospin trapping. Our results show that aromatic amines generating phenyl radical metabolites in presence of HRP/H2O2 oxidise PUFA to form lipid peroxides but do not oxidise GSH. Aromatic amines which do not form detectable phenyl radical oxidized only GSH. Furthermore, ESR and gel-electrophoresis studies showed that PUFAs are target for phenyl radical metabolite and scavenge them, and prevent the protein oxidation induced by phenyl radical. In conclusion, these results suggest a possible mechanism for aromatic amine induced agranulocytosis.
Language
English
DOI
doi:10.7939/R3R394
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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