We recently demonstrated that V(5+) 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 V(5+) (as
ammonium metavanadate, NH(4)VO(3)) 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 V(5+) treatment in a dose-dependent manner. Investigating the effect of co-exposure to V(5+) and
TCDD at transcriptional levels revealed that V(5+) 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 V(5+) in modifying
CYP1A1 gene expression through this mechanism. On the other hand, at the posttranslational level, V(5+) was able to significantly decrease
CYP1A1 protein half-life contributing to the inconsistency between catalytic activity and transcriptional level. Importantly, we showed that V(5+) did not significantly alter the
heme oxygenase-1 mRNA level, thus eliminating any possibility that V(5+) might have decreased
CYP1A1 activity through affecting its
heme content. This study demonstrates for the first time that V(5+) downregulates the expression of
CYP1A1 at the transcriptional, posttranscriptional and posttranslational mechanisms in the human
hepatoma HepG2 cells.