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Received for publication September 9, 2004.
Revised November 29, 2004.
Accepted for publication November 30, 2004.
Polycyclic aromatic hydrocarbons (PAHs) and heavy metals are often environmental co-contaminants that could interact to alter PAH carcinogenicity. The heavy metal, arsenite, and the PAH, benzo[k]fluoranthene (BKF), were used as prototypes to investigate, in human HepG2 cells, mechanisms whereby the bioactivation of BKF by human CYP1A1 could be diminished by arsenite-mediated decreases in CYP1A1 induction by BKF. To determine whether arsenite down regulates CYP1A1 transcription, quantitative Real Time RT-PCR assays and luciferase reporter gene expression assays were used with HepG2 cells treated with BKF and arsenite, separately and as a mixture. BKF (0.5 µM) and arsenite (5 µM) markedly decreased BKF-mediated induction of CYP1A1 mRNA by 45%. Plasmids containing the CYP1A1 promoter region (pHu-1A1-FL) were induced 7.4-fold over vehicle by BKF (0.5 µM), while arsenite (1, 2.5 or 5 µM) decreased reporter gene expression by 46%, 45% and 61%, respectively. The plasmid, pHu-1A1-D100-FL, lacked XRE sites at -1061 and -981 and showed greater responsiveness relative to pHu-1A1-FL, by 1.7-fold. BKF (0.5 µM) and arsenite (1, 2.5 or 5 µM) decreased reporter gene expression by 0%, 27% and 39%, respectively. Arsenite is stable for at least 48 h in the HepG2 cells medium with respect to its ability to diminish CYP1A1 BKF induction. Arsenite did not affect BKF induction directly through XRE sites nor did if affect the stability of CYP1A1 mRNA. Thus, arsenite affects the transcriptional regulation of the BKF-mediated induction of CYP1A1, and could diminish PAH carcinogenicity by decreasing bioactivation by CYP1A1.
Key words:
cytochrome P450, human CYP enzymes, induction, metal toxicology, polycyclic aromatic hydrocarbons
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