PT  - JOURNAL ARTICLE
AU  - Anwar Anwar-Mohamed
AU  - Ayman O. S. El-Kadi
TI  - Down-Regulation of the Carcinogen-Metabolizing Enzyme Cytochrome P450 1a1 by Vanadium
AID  - 10.1124/dmd.108.021154
DP  - 2008 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1819--1827
VI  - 36
IP  - 9
4099  - http://dmd.aspetjournals.org/content/36/9/1819.short
4100  - http://dmd.aspetjournals.org/content/36/9/1819.full
SO  - Drug Metab Dispos2008 Sep 01; 36
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics