Effects of vanadium (sodium metavanadate) and aflatoxin-B1 on cytochrome p450 activities, DNA damage and DNA methylation in human liver cell lines.

Vanadium is considered as "possibly carcinogenic to humans" (V2O5, IARC Group 2B), yet uncertainties persist related to the toxicity mechanisms of the multiple forms of vanadium. Exposure to vanadium often co-occurs with other metals or with organic compounds that can be transformed by cytochrome p450 (CYP) enzymes into DNA-reactive carcinogens. Therefore, effects of a soluble form of vanadium (sodium metavanadate, NaVO3) and aflatoxin-B1 (AFB1) were tested separately and together, for induction of CYP activities, DNA damage (γH2AX and DNA alkaline unwinding assays), and DNA methylation changes (global genome and DNA repeats) in HepaRG or HepG2 liver cell lines. NaVO3 (≥ 2.3 μM) reduced CYP1A1 and CYP3A4 activities and induced DNA damage, butcaused important cell proliferation only in HepaRG cells. As a binary mixture, NaVO3 did not modify the effects of AFB1. There was no reproducible effect of NaVO3 (<21 μM) on DNA methylation in AluYb8, satellite-α, satellite-2, and by the luminometric methylation assay, but DNA methylation flow-cytometry signals in HepG2 cells (25-50 μM) increased at the G1 and G2 cell cycle phases. In conclusion, cell lines responded differently to NaVO3 supporting the importance of investigating more than one cell line, and a carcinogenic role of NaVO3 might reside at low concentrations by stimulating the proliferation of tumorigenic cells.