Down-regulation of the carcinogen-metabolizing enzyme cytochrome P450 1a1 by vanadium

Area of Science:

• Toxicology
• Molecular Biology
• Biochemistry

Background:

• Vanadium (V(5+)) is a heavy metal with toxicological effects and potential anticancer properties.
• The anticancer mechanisms of vanadium are not fully understood.
• The aryl hydrocarbon receptor (AhR) pathway regulates genes involved in xenobiotic metabolism, including cytochrome P450 1a1 (Cyp1a1).

Purpose of the Study:

• To investigate the effect of V(5+) on the expression of the AhR-regulated gene Cyp1a1.
• To elucidate the specific step(s) in the AhR signal transduction pathway affected by V(5+).

Main Methods:

• Hepa 1c1c7 cells were treated with V(5+) (ammonium metavanadate) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
• Cyp1a1 mRNA, protein, and activity levels were measured.
• AhR-dependent luciferase reporter gene expression was assessed.
• Nuclear accumulation of AhR and AhR/Arnt/XRE complex formation were analyzed.
• Ecto-ATPase activity was measured.

Main Results:

• V(5+) significantly reduced TCDD-induced Cyp1a1 mRNA, protein, and activity in a dose-dependent manner.
• V(5+) inhibited TCDD-mediated induction of AhR-dependent luciferase reporter gene expression.
• V(5+) did not affect TCDD-induced cytosolic AhR activation or its transformation to a DNA-binding form.
• V(5+) inhibited the nuclear accumulation of liganded AhR and subsequent AhR/Arnt/XRE complex formation.
• V(5+)-mediated inhibition correlated with decreased ecto-ATPase activity.
• V(5+) did not affect the stability of existing Cyp1a1 mRNA or protein.

Conclusions:

• V(5+) down-regulates Cyp1a1 expression at the transcriptional level.
• The mechanism involves inhibition of nuclear translocation of the liganded AhR and subsequent complex formation.
• This inhibition is linked to an ATP-dependent process, potentially involving ecto-ATPase activity.
• V(5+) does not affect Cyp1a1 expression post-transcriptionally or post-translationally.