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Identifying Aryl Hydrocarbon Receptor Modulators from a Natural Source

  • Author / Creator
    El Gendy, Mohamed, A M
  • 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.

  • Subjects / Keywords
  • Graduation date
    2012-09
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3T40P
  • 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
    Doctoral
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Velazquez, Carlos (Pharmacy and Pharmaceutical Sciences,University of Alberta)
    • Baker, Glen (Psychiatry, University of Alberta)
    • Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
    • Totah, Rheem (Medicinal chemistry, University of Washington)
    • El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences,University of Alberta)
    • Siraki, Arno (Pharmacy and Pharmaceutical Sciences,University of Alberta)