Reactive oxygen species (ROS) generated by metals play an important role in the etiology of various diseases and cancers. Metals generate ROS by two general pathways. One is direct interaction of metals with cellular molecules without involvement of signaling transduction. For example, flavenzymes reduce Cr(VI) to Cr(V) in the presence of NAD(P)H; oxygen is reduced to superoxide radical that generates hydrogen peroxide by dismutation; Cr(VI) also reacts with hydrogen to generate hydroxyl radicals by a Fenton-like reaction. Alternatively, metals may generate ROS by stimulation of cells; this involves expression of NADPH oxidase by various signal molecules. Metals may induce various cellular responses by ROS mediated reactions. For example, Cr(VI) may activate MAPKs and their down stream targets, such as NF-EB and AP-1. NF-EB inhibits of Cr(VI)-induced cell death. Inhibition of NF-EB by IKKa-KM or IKKa deficiency results in spontaneous cleavage of Bcl-xL antiapoptotic protein due to elevated caspase-3 activity. Exogenous antiapoptotic proteins (cIAP1), a caspase inhibitor, partially inhibits Cr(VI)-induced cell death; thus caspases are involved in Cr(VI)-induced cell death. In response to Cr(VI), p53 protein is phosphorylated at Ser15 and acetylated at Lys382. ERK phosphorylates p53 at Ser15 site. Via ERK and p38, Cr(VI) also upregulates p21 and cdc2 and causes degradation of cdc25C, leading to growth arrest at G2/M. Specific ROS affect specific MAPKs and cell growth regulatory proteins with different potencies. Cr(VI) induces hypoxia-inducible factor-1 (HIF-1) activity by specific expression of HIF-1a but not HIF-1a subunit and increases vascular endothelial growth factor (VEGF) expression. p38 signaling is required for Cr(VI)- induced HIF-a expression, but PI3-K and ERK are not required for Cr(VI)-induced HIF-1 expression. Hydrogen peroxide is responsible for HIF-1 induction and VEGF expression. By ROS-mediated mechanisms, As, Ni and V also activate MAPKs and other oxidative responsive proteins to induce cellular responses, such as activation of PI3-K/Akt pathway, NF-EB, AP-1, p53, nuclear factor of activated T cells (NFAT), HIF-1, cell cycle arrest, and apoptosis.
The Toxicologist. Society of Toxicology 45th Annual Meeting and ToxExpo, March 5-9, 2006, San Diego, California