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Modulation of Aryl Hydrocarbon Receptor Regulated-Genes by Mercury Open Access


Other title
Modulation of Drug Metabolizing Enzymes by Mercury
AhR, Mercury, TCDD CYP1A1, NQO1, in vitro and in vivo
Type of item
Degree grantor
University of Alberta
Author or creator
Amara, Issa
Supervisor and department
El-Kadi, Ayman (Pharmaceutical Sciences)
Examining committee member and department
Velazquez, Carlos (Pharmaceutical Sciences)
Siraki, Arno (Pharmaceutical Sciences)
Baker, Glen (Department of Psychiatry)
Klotz, Lars-Oliver (Pharmaceutical Sciences)
Faculty of Pharmacy and Pharmaceutical Sciences
Pharmaceutical Sciences
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Aryl hydrocarbon receptor (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and metals, such as mercury (Hg), are environmental co-contaminants with multiple biological consequences. Therefore, the objectives of the current dissertation were to: 1) examine the potential effect of co-exposure to Hg and TCDD on the expression of the AhR-regulated phase I and phase II genes in HepG2 cells, isolated mouse hepatocytes, and in vivo in the liver, kidney, lung, and heart of C57Bl/6J mice, and 2) to explore the molecular mechanisms involved in this modulation. In vitro, Hg2+ significantly inhibited the TCDD-mediated induction of CYP1A1 at the mRNA, protein, and catalytic activity levels. Furthermore, co-exposure to Hg2+ and TCDD significantly decreased the TCDD-mediated induction of AhR-dependent luciferase reporter gene expression. At the post-translational level, Hg2+ significantly decreased the protein half-life, and increased the expression of heme oxygenase-1 (HO-1), which coincided with further decrease in the CYP1A1 catalytic activity levels. With regard to NQO1, Hg2+ increased its expression at the mRNA, protein, and activity levels in the absence and presence of both NQO1 inducers, TCDD and Sulforaphane (SUL), which coincided with increased nuclear accumulation of Nrf2 protein. Hg2+ was able to induce the antioxidant responsive element (ARE)-dependent luciferase reporter gene expression in an Nrf2 dependent mechanism. In vivo, Hg2+ differentially modulated phase I and phase II AhR-regulated genes at the constitutive and inducible levels. Interestingly, Hg2+ increased serum hemoglobin (Hb) levels in mice treated for 24 h with Hg2+. Upon treatment of isolated hepatocytes with Hb alone, there was an increase in the AhR-dependent luciferase activity with a subsequent increase in Cyp1a1 protein and catalytic activity levels. In conclusion, the present study demonstrates that exposure to Hg2+ and TCDD in vitro may decrease TCDD-mediated carcinogenicity by decreasing the induction of CYP1A1 and increasing the induction of NQO1. However; at the in vivo level, Hg2+ modulates the constitutive and inducible AhR-regulated genes in a time-, tissue- and, AhR-regulated enzyme specific manner. In addition, at the in vitro level HO-1 and Nrf2 are involved in the modulation of CYP1A1 and NQO1 respectively, while Hb was implicated as an in vivo specific modulator of Cyps.
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
Amara, I.E., Anwar-Mohamed, A., Abdelhamid, G., El-Kadi, A.O., 2012. Effect of mercury on aryl hydrocarbon receptor-regulated genes in the extrahepatic tissues of C57BL/6 mice. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 50, 2325-2334. Amara, I.E., Anwar-Mohamed, A., Abdelhamid, G., El-Kadi, A.O., 2013a. Mercury modulates the cytochrome P450 1a1, 1a2 and 1b1 in C57BL/6J mice: in vivo and in vitro studies. Toxicology and applied pharmacology 266, 419-429. Amara, I.E., Anwar-Mohamed, A., El-Kadi, A.O., 2010. Mercury modulates the CYP1A1 at transcriptional and posttranslational levels in human hepatoma HepG2 cells. Toxicology letters 199, 225-233. Amara, I.E., Anwar-Mohamed, A., El-Kadi, A.O., 2013b. Posttranslational mechanisms modulating the expression of the cytochrome P450 1A1 gene by methylmercury in HepG2 cells: A role of heme oxygenase-1. Toxicology letters. Amara, I.E., El-Kadi, A.O., 2011. Transcriptional modulation of the NAD(P)H:quinone oxidoreductase 1 by mercury in human hepatoma HepG2 cells. Free radical biology & medicine 51, 1675-1685.

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File title: In the current study, Hg2+ increased NQO1 mRNA at the constitutive and the inducible levels. Therefore, it was of interest to examine the time-dependent effects of Hg2+ on the Nrf2 mRNA and protein levels. Our results demonstrated that Hg2+ ...
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