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Research ArticleArticle

Down-Regulation of the Carcinogen-Metabolizing Enzyme Cytochrome P450 1a1 by Vanadium

Anwar Anwar-Mohamed and Ayman O. S. El-Kadi
Drug Metabolism and Disposition September 2008, 36 (9) 1819-1827; DOI: https://doi.org/10.1124/dmd.108.021154
Anwar Anwar-Mohamed
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Ayman O. S. El-Kadi
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Abstract

Vanadium (V5+), a heavy metal contaminant with important toxicological consequences, has received considerable attention as an anticancer agent, although the mechanisms remain unknown. As a first step to investigate these mechanisms, we examined the effect of V5+ (as ammonium metavanadate, NH4VO3) on the expression of the aryl hydrocarbon receptor (AhR)-regulated gene: cytochrome P450 1a1 (Cyp1a1) at each step of the AhR signal transduction pathway, using Hepa 1c1c7 cells. Our results showed a significant reduction in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of Cyp1a1 mRNA, protein and activity levels after V5+ treatments in a dose-dependent manner. Investigation of the effect of coexposure to V5+ and TCDD at transcriptional levels revealed that V5+ significantly inhibited TCDD-mediated induction of AhR-dependent luciferase reporter gene expression. Furthermore, despite not affecting the direct activation of the cytosolic AhR by TCDD and subsequently transforming it to a DNA-binding form, V5+ inhibited the nuclear accumulation of liganded AhR and subsequent formation of the AhR/aryl hydrocarbon nuclear translocator (Arnt)/xenobiotic responsive element (XRE) complex. Importantly, the V5+-mediated inhibition of AhR/Arnt/XRE complex formation coincided with a significant decrease in ecto-ATPase activity. Looking at the post-transcriptional and post-translational effects of V5+ on existing Cyp1a1 mRNA and protein levels, we showed that V5+ did not affect Cyp1a1 mRNA or protein stability, thus eliminating possible role of V5+ in modifying Cyp1a1 gene expression through these mechanisms. This study provides the first evidence that V5+ down-regulates the expression of Cyp1a1 at the transcriptional level through an ATP-dependent mechanism.

Footnotes

  • This work was supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant RGPIN 250139-07 to A.O.S.E.-K. A.A.-M. is recipient of a Mike Wolowyk Graduate Scholarship award.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.021154.

  • ABBREVIATIONS: AhR, aryl hydrocarbon receptor; Arnt, aryl hydrocarbon receptor nuclear translocator; XRE, xenobiotic responsive element; Cyp1a1, cytochrome P450 1a1; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; V5+, vanadium; pGudluc1.1, XRE-luciferase reporter plasmid; EMSA, electrophoretic mobility shift assay; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; CHX, cycloheximide; Act-D, actinomycin D; DMSO, dimethylsulfoxide; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; HO-1, heme oxygenase-1; PAGE, polyacrylamide gel electrophoresis; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; EROD, 7-ethoxyresorufin O-deethylase; NF-κB, nuclear factor-κB.

    • Received February 20, 2008.
    • Accepted June 4, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (9)
Drug Metabolism and Disposition
Vol. 36, Issue 9
1 Sep 2008
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Research ArticleArticle

Down-Regulation of the Carcinogen-Metabolizing Enzyme Cytochrome P450 1a1 by Vanadium

Anwar Anwar-Mohamed and Ayman O. S. El-Kadi
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1819-1827; DOI: https://doi.org/10.1124/dmd.108.021154

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Research ArticleArticle

Down-Regulation of the Carcinogen-Metabolizing Enzyme Cytochrome P450 1a1 by Vanadium

Anwar Anwar-Mohamed and Ayman O. S. El-Kadi
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1819-1827; DOI: https://doi.org/10.1124/dmd.108.021154
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