A large portion of this work has been written up for publication and will be submitted shortly. The animals exposed to DMBA and TPA in this experiment are finally showing a positive response, but preliminary data suggest that arsenic in the drinking water may reduce skin papilloma formation in the DMBA and TPA-treated mice rather than enhancing the carcinogenesis process, as was predicted. However, low concentrations of AsIII can cause significant changes in cellular GSH levels and in the relative activity and gene expression of a variety of redox active enzymes either in cultured human keratinocytes or human fibroblasts. These results show that even low, relatively non-toxic concentrations of arsenic can directly modulate cellular redox activity which, in turn, may alter cellular signaling and other aspects of intermediary metabolism and thereby contribute to the carcinogenic process. However, we have also found, contrary to earlier hypotheses, that these changes are not brought about by the direct inhibition of redox-related enzymes by inorganic As or arsenic metabolites.
Most enzymes are quite insensitive to physiological concentrations of arsenic.
Direct enzyme inhibition is only seen at high arsenic concentrations or with arsenic complexes found at very low concentrations in skin cells. It is proposed instead that arsenic produces alterations in the activity of these redox regulating enzymes by initiating changes in the regulation of the genes. The means whereby arsenic initiates these changes is not yet established and we are now investigating the specific role of reactive oxygen species in the induction of gene expression and in As-induced cellular toxicity. These findings need to be incorporated into any reasonable mechanism-based model for risk assessment. For Aim 3, we are examining the hypothesis that arsenic acts as a progressor or co-promoter in the production of skin cancer and evaluating the role of GSH in this process.