Differential Modulation of Aryl Hydrocarbon Receptor Regulated Genes by Chromium

  • Author / Creator
    Asiri, Abdulrahman Y
  • Several studies have examined the toxic effects of individual aryl hydrocarbon receptor (AhR) ligands, yet there are relatively few reports of the combined toxic effects of AhR ligands and other environmental co-contaminants, such as heavy metals. Chromium (Cr+6) is one of the major environmental toxic metal contaminants and a potent human toxin, mutagen, and carcinogen. Heavy metals alter the carcinogenicity of AhR ligands by modulating the cytochrome P450 1 (Cyp1) enzyme; however, the mechanism(s) remain unresolved. The objective of the current study was to investigate the effect of Cr+6 on expression and activity, of Cyp1a1, NQO1 and HO-1 in C57BL/6 mouse liver. C57BL/6 mice were injected intraperitoneally with Cr+6 (20 mg/kg) in the absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (15 μg/kg) for 24 h. The mice were segregated into 4 experimental groups. The first group was control mice, and they received saline plus corn oil. The second group was Cr+6-treated mice, and they received Cr+6 dissolved in saline plus corn oil. The third group was TCDD-treated mice, and they received TCDD dissolved in corn oil plus saline. The fourth group was Cr+6 plus TCDD–treated mice, and they received Cr+6 dissolved in saline plus TCDD dissolved in corn oil. Moreover, real-time PCR and Western blot were used to measure mRNA and protein expression, respectively. EROD was used to measure Cyp1a1 activity. Cr+6 alone did not significantly alter Cyp1a1, NQO1 or HO-1 at mRNA, protein, or catalytic activity levels. Upon co-exposure to Cr+6 and TCDD, Cr+6 significantly inhibited the TCDD-mediated induction of the Cyp1a1 mRNA, protein, or catalytic activity levels, whereas it significantly potentiated the induction of NQO1 and HO-1 mediated by TCDD at the mRNA, protein and catalytic activity levels at 24 h. We demonstrated that Cr+6 inhibits the AhR-ligand -mediated effect on the carcinogen-activating enzymes whereas it potentiated the carcinogen detoxifying enzymes NQO1 and HO-1.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • 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
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Sciences)
    • Baker, Glen (Faculty of Psychiatry)
    • Siraki, Arno (Faculty of Pharmacy and Pharmaceutical Sciences)