Vanadate induces p53 transactivation through hydrogen peroxide and causes apoptosis

Vanadium is a metal widely distributed in the environment. Although vanadat e-containing compounds exert potent toxic effects on a wide variety of biol ogical systems, the mechanisms controlling vanadate-induced adverse effects remain to be elucidated. The present study investigated the vanadate-induc ed p53 activation and involvement of reactive oxygen species (ROS) in p53 a ctivation as well as the role of p53 in apoptosis induction by vanadate. Ex posure of mouse epidermal JB6 cells to vanadate led to transactivation of p 53 activity in a time- and dose-dependent manner. It also caused mitochondr ial damage, apoptosis, and generated ROS. Scavenging of vanadate-induced H2 O2 by N-acetyl-L-cysteine (a general antioxidant) or catalase (a specific H 2O2 inhibitor), or the chelation of vanadate by deferoxamine, resulted in i nhibition of p53 activation and cell mitochondrial damage. In contract, an increase in H2O2 generation in response to superoxide dismutase or NADPH en hanced these effects caused by vanadate. Furthermore, vanadate-induced apop tosis occurred in cells expressing wild-type p53 (p53+/+) but was very weak in p53-deficient (p53-/-) cells. These results demonstrate that vanadate i nduces p53 activation mainly through H2O2 generation, and this activation i s required for vanadate-induced apoptosis.