Chromium (VI)-induced oxidative stress, apoptotic cell death and modulation of p53 tumor suppressor gene

Chromium (VI) is a widely used industrial chemical, extensively used in pai nts, metal finishes, steel including stainless steel manufacturing, alloy c ast irons, chrome, and wood treatment. On the contrary, chromium (III) salt s such as chromium polynicotinate, chromium chloride and chromium picolinat e, are used as micronutrients and nutritional supplements, and have been de monstrated to exhibit a significant number of health benefits in rodents an d humans. However, the cause for the hexavalent chromium to induce cytotoxi city is not entirely understood. A series of in vitro and in vivo studies h ave demonstrated that chromium (VI) induces an oxidative stress through enh anced production of reactive oxygen species (ROS) leading to genomic DNA da mage and oxidative deterioration of lipids and proteins. A cascade of cellu lar events occur following chromium (VI)-induced oxidative stress including enhanced production of superoxide anion and hydroxyl radicals, increased l ipid peroxidation and genomic DNA fragmentation, modulation of intracellula r oxidized states, activation of protein kinase C, apoptotic cell death and altered gene expression. In this paper, we have demonstrated concentration - and time-dependent effects of sodium dichromate (chromium (VI) or Cr (VI) ) on enhanced production of superoxide anion and hydroxyl radicals, changes in intracellular oxidized states as determined by laser scanning confocal microscopy, DNA fragmentation and apoptotic cell death (by flow cytometry) in human peripheral blood mononuclear cells. These results were compared wi th the concentration-dependent effects of chromium (VI) on chronic myelogen ous leukemic K562 cells and J774A.1 murine macrophage cells. Chromium (VI)- induced enhanced production of ROS, as well as oxidative tissue and DNA dam age were observed in these cells. More pronounced effect was observed on ch ronic myelogenous leukemic K562 cells and J774A.1 murine macrophage cells. Furthermore, we have assessed the effect of a single oral LD50 dose of chro mium (VI) on female C57BL/6Ntac and p53-deficient C57BL/6TSG p53 mice on en hanced production of superoxide anion, lipid peroxidation and DNA fragmenta tion in the hepatic and brain tissues. Chromium (VI)-induced more pronounce d oxidative damage in p53 deficient mice. This in vivo study highlighted th at apoptotic regulatory protein p53 may play a major role in chromium (VI)- induced oxidative stress and toxicity. Taken together, oxidative stress and oxidative tissue damage, and a cascade of cellular events including modula tion of apoptotic regulatory gene p53 are involved in chromium (VI)-induced toxicity and carcinogenesis.