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Research ArticleArticle

MECHANISMS OF ARSENITE-MEDIATED DECREASES IN BENZO[K]FLUORANTHENE-INDUCED HUMAN CYTOCHROME P4501A1 LEVELS IN HEPG2 CELLS

Erin E. Bessette, Michael J. Fasco, Brian T. Pentecost and Laurence S. Kaminsky
Drug Metabolism and Disposition March 2005, 33 (3) 312-320; DOI: https://doi.org/10.1124/dmd.104.002212
Erin E. Bessette
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Michael J. Fasco
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Brian T. Pentecost
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Laurence S. Kaminsky
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Abstract

Polycyclic aromatic hydrocarbons (PAHs) and heavy metals are often environmental cocontaminants that could interact to alter PAH carcinogenicity. The heavy metal, arsenite, and the PAH, benzo[k]fluoranthene, were used as prototypes to investigate, in human HepG2 cells, mechanisms whereby the bioactivation of benzo[k]fluoranthene by human CYP1A1 could be diminished by arsenite-mediated decreases in CYP1A1 induction by benzo[k]fluoranthene. To determine whether arsenite down-regulates CYP1A1 transcription, quantitative real-time reverse transcriptase-polymerase chain reaction assays and luciferase reporter gene expression assays were used with HepG2 cells treated with benzo[k]fluoranthene and arsenite, separately and as a mixture. Benzo[k]fluoranthene (0.5 μM) and arsenite (5 μM) markedly decreased benzo[k]fluoranthene-mediated induction of CYP1A1 mRNA by 45%. Plasmids containing the CYP1A1 promoter region (pHu-1A1-FL) were induced 7.4-fold over vehicle by benzo[k]fluoranthene (0.5 μM), whereas arsenite (1, 2.5, or 5 μM) decreased reporter gene expression by 46%, 45%, and 61%, respectively. The plasmid, pHu-1A1-Δ100-FL, lacked xenobiotic response element (XRE) sites at –1061 and –981 and showed greater responsiveness relative to pHu-1A1-FL, by 1.7-fold. Benzo[k]fluoranthene (0.5 μM) and arsenite (1, 2.5, or 5 μM) decreased reporter gene expression by 0%, 27%, and 39%, respectively, relative to expression levels produced by benzo[k]fluoranthene alone. Arsenite is stable for at least 48 h in the HepG2 cell medium with respect to its ability to diminish CYP1A1 benzo[k]fluoranthene induction. Arsenite did not affect benzo[k]fluoranthene induction directly through XRE sites, nor did it affect the stability of CYP1A1 mRNA. Thus, arsenite affects the transcriptional regulation of the benzo[k]fluoranthene-mediated induction of CYP1A1 and could diminish PAH carcinogenicity by decreasing bioactivation by CYP1A1.

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

  • doi:10.1124/dmd.104.002212.

  • ABBREVIATIONS: P450, cytochrome P450; DMSO, dimethyl sulfoxide; RT-PCR, reverse transcriptase-polymerase chain reaction; PAH, polycyclic aromatic hydrocarbon; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; EROD, 7-ethoxyresorufin O-deethylase; BAP, benzo[a]pyrene; NRE, negative regulatory element; NF1, nuclear factor 1; BTE, basic transcription element; FL, firefly luciferase; XRE, xenobiotic response element.

    • Received September 9, 2004.
    • Accepted November 30, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (3)
Drug Metabolism and Disposition
Vol. 33, Issue 3
1 Mar 2005
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Research ArticleArticle

MECHANISMS OF ARSENITE-MEDIATED DECREASES IN BENZO[K]FLUORANTHENE-INDUCED HUMAN CYTOCHROME P4501A1 LEVELS IN HEPG2 CELLS

Erin E. Bessette, Michael J. Fasco, Brian T. Pentecost and Laurence S. Kaminsky
Drug Metabolism and Disposition March 1, 2005, 33 (3) 312-320; DOI: https://doi.org/10.1124/dmd.104.002212

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Research ArticleArticle

MECHANISMS OF ARSENITE-MEDIATED DECREASES IN BENZO[K]FLUORANTHENE-INDUCED HUMAN CYTOCHROME P4501A1 LEVELS IN HEPG2 CELLS

Erin E. Bessette, Michael J. Fasco, Brian T. Pentecost and Laurence S. Kaminsky
Drug Metabolism and Disposition March 1, 2005, 33 (3) 312-320; DOI: https://doi.org/10.1124/dmd.104.002212
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