TOXI 104 |
| Ascorbate is a well known intracellular antioxidant. In addition to scavenging free radicals, it serves to maintain iron in the Fe(II) state in numerous iron-containing dioxygenases (IDs). Among them is a family of enzymes involved in posttranslational hydroxylation of cellular proteins, including collagens I-XXVII and HIF-1alpha and 2alpha proteins. A number of carcinogenic metals including cobalt(II), nickel(II) and chromium(VI) can facilitate ascorbate oxidation to recyclable forms of either ascorbate free radical or dehydroascorbate. Besides ascorbate oxidation, exposure of cells to metals also affects ascorbate uptake via sodium-dependent transporter SVCT2. As a result, exposure to metals substantially depletes intracellular ascorbate stores. The decrease in intracellular levels of ascorbate inhibits IDs activity and causes the loss of protein hydroxylation. The loss of collagen hydroxylation may affect extracellular matrix formation. The loss of HIF-1alpha protein hydroxylation leads to the accumulation of this protein and activation of HIF-1-dependent transcription. Thus, exposure to metals will result in disorganization of extracellular matrix and shift cellular metabolism to a glycolytic pathway, producing typical features of the tumor phenotype. |
|
Metal Carcinogenesis: New Concepts
2:00 PM-5:00 PM, Wednesday, 13 September 2006 Moscone Center -- Room 308, Oral
Division of Chemical Toxicology |