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Identifying Aryl Hydrocarbon Receptor Modulators from a Natural Source Open Access

Descriptions

Other title
Subject/Keyword
Cytochrome P450 1A1
harmol
Aryl Hydrocarbon Receptor
harmalol
harmine
Peganum harmala
Aryl Hydrocarbon Receptor antagonists from natural source
harmaline
harman
Chemoprevention
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
El Gendy, Mohamed, A M
Supervisor and department
El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Totah, Rheem (Medicinal chemistry, University of Washington)
Velazquez, Carlos (Pharmacy and Pharmaceutical Sciences,University of Alberta)
El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences,University of Alberta)
Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
Baker, Glen (Psychiatry, University of Alberta)
Siraki, Arno (Pharmacy and Pharmaceutical Sciences,University of Alberta)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2012-09-10T17:07:09Z
Graduation date
2012-09
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Dioxins are widespread environmental contaminants that have been linked to a variety of deleterious effects on human health including increased cancer rates via aryl hydrocarbon receptor (AhR)-dependent mechanism. AhR is a transcription factor that regulates the expression of the carcinogen-activating enzyme, cytochrome P450 1A1 (CYP1A1). Activation of AhR and its regulated gene, CYP1A1, have been correlated with the incidence of several cancers. Therefore, the use of AhR antagonists has been proposed as a promising chemopreventative approach. Nonetheless, most of the currently used AhR antagonists are not specific to AhR and some of them act as partial agonists. Therefore, the search for new AhR antagonists is still in progress. The specific objectives of the present work were to identify new AhR modulators from a natural source. In this regard, first we demonstrated that Peganum harmala, a common traditional plant in Middle East, and North Africa, significantly inhibited the dioxin-mediated induction of CYP1A1 at mRNA, protein and activity levels using human and mouse hepatoma cells. The role of AhR was confirmed using AhR-dependent luciferase assay and electrophoretic mobility shift assay. Additionally, we identified two β-carboline alkaloids (harmine and harmaline) as the active constituents of the plant extract. Second, we demonstrated that harman, a common β-carboline in several foods and drinks and the parent structure of harmine, significantly induced CYP1A1 mainly through an AhR-dependent mechanism. Third, the active constituents of Peganum harmala extract, harmine and harmaline, and their metabolites, harmol and harmalol, significantly decreased the dioxin-mediated induction of CYP1A1 at mRNA, protein and activity levels via transcriptional (through AhR) and post-translational (through ubiquitin-proteasomal pathway as well as a direct inhibitory effect on CYP1A1 enzyme). Additionally, we demonstrated that harmine, harmol, and harmalol can act as direct antagonists for AhR, whereas harmalol affected AhR activation without a direct interfering with AhR binding to its ligands. Finally, we confirmed the effect of harmine and harmaline on dioxin-mediated induction of Cyp1a1 in vivo using the responsive C57BL/6 mouse strain. In conclusion, our data clearly demonstrate the promising effects of Peganum harmala, harmine, harmol, harmaline, and harmalol to prevent the toxicity and carcinogenicity of several AhR ligands.
Language
English
DOI
doi:10.7939/R3T40P
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.
Citation for previous publication
El Gendy, M. A., Soshilov, A. A., Denison, M. S., El-Kadi, A. O. Transcriptional and posttranslational inhibition of dioxin-mediated induction of CYP1A1 by harmine and harmol. Toxicol Lett 2012, 208:51-61.El Gendy, M. A., El-Kadi, A. O. Harman induces CYP1A1 enzyme through an aryl hydrocarbon receptor mechanism. Toxicol Appl Pharmacol 2010, 249:55-64.El Gendy, M. A., Soshilov, A. A., Denison, M. S., El-Kadi, A. O. Harmaline and harmalol inhibit the carcinogen-activating enzyme CYP1A1 via transcriptional and posttranslational mechanisms. Food Chem Toxicol 2012, 50: 353-362.El Gendy, M. A., Somayaji, V., El-Kadi, A. O. Peganum harmala L. is a candidate herbal plant for preventing dioxin mediated effects. Planta Med 2010, 76(7):671-677.

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