Mitomycin C and diepoxybutane action mechanisms and FANCC protein functions: further insights into the role for oxidative stress in Fanconi's anaemiaphenotype

Evidence for redox-dependent toxicities of mitomycin C (MMC) and diepoxybut ane (DEB), through different mechanisms, has been related to the phenotypic defect(s) of Fanconi's anaemia (FA) cells, due to their excess sensitivity to these agents. Recent data have pointed to interactions of the FANCC pro tein (encoded by the FA complementation group C gene, FA-C) with NADPH cyto chrome P450 reductase and glutathione S-transferase (GST), two activities i nvolved in either triggering or detoxifying reactive intermediates, includi ng xenobiotics and reactive oxygen species. A body of evidence points to: ( i) oxygen hypersensitivity of FA cells; (ii) oxygen-dependent MMC and DEB t oxicity; (iii) excess oxidative DNA damage in FA cells; and (iv) DEB-induce d glutathione depletion and GST inhibition. The available evidence corrobor ates the previously suggested role for oxidative stress in FA phenotype and disease progression, shedding new light on the redox-dependent mechanisms in MMC and DEB toxicities, and suggesting a direct association of oxidative stress with the primary genetic defect in FA.