Title

Transcriptional and posttranscriptional regulation of CYP1A1 by vanadium in human hepatoma HepG2 cells

Document Type

Article

Publication Date

10-1-2010

Abstract

We recently demonstrated that V5+ downregulates 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of Cyp1a1 mRNA, protein, and catalytic activity levels in Hepa 1c1c7 cells through transcriptional mechanism. Therefore, it is important to investigate whether similar changes occur in humans. For this purpose, we examined the effect of V5+ (as ammonium metavanadate, NH4VO3) on the expression of aryl hydrocarbon receptor (AhR)-regulated gene; cytochrome P450 1A1 (CYP1A1) at each step of the AhR signal transduction pathway in human hepatoma HepG2 cells. Our results show a significant reduction in TCDD-mediated induction of CYP1A1 mRNA, protein, and activity levels after V5+ treatment in a dose-dependent manner. Investigating the effect of co-exposure to V5+ and TCDD at transcriptional levels revealed that V5+ significantly inhibited TCDD-mediated induction of AhR-dependent luciferase reporter gene expression. Looking at the posttranscriptional level, V 5+ did not affect CYP1A1 mRNA stability, thus eliminating the possible role of V5+ in modifying CYP1A1 gene expression through this mechanism. On the other hand, at the posttranslational level, V5+ was able to significantly decrease CYP1A1 protein half-life contributing to the inconsistency between catalytic activity and transcriptional level. Importantly, we showed that V5+ did not significantly alter the heme oxygenase-1 mRNA level, thus eliminating any possibility that V5+ might have decreased CYP1A1 activity through affecting its heme content. This study demonstrates for the first time that V5+ downregulates the expression of CYP1A1 at the transcriptional, posttranscriptional and posttranslational mechanisms in the human hepatoma HepG2 cells. © 2010 Springer Science+Business Media B.V.

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