Guanine sulphinate is a major stable product of photochemical oxidation of DNA 6-thioguanine by UVA irradiation

Abstract

The DNA of patients taking the immunosuppressant and anticancer drugs azathioprine or 6-mercaptopurine contains 6-thioguanine (6-TG). The skin of these patients is selectively sensitive to ultraviolet A radiation (UVA) and they suffer an extremely high incidence of sunlight-induced skin cancer with long-term treatment. DNA 6-TG interacts with UVA to generate reactive oxygen species, which oxidize 6-TG to guanine sulphonate (GSO3). We suggested that GSO3 is formed via the reactive electrophilic intermediates, guanine sulphenate (GSO) and guanine sulphinate (GSO2). Here, GSO2 is identified as a significant and stable UVA photoproduct of free 6-TG, its 2′-deoxyribonucleoside, and DNA 6-TG. Mild chemical oxidation converts 6-TG into GSO2, which can be further oxidized to GSO3-a stable product that resists further reaction. In contrast, GSO2 is converted back to 6-TG under mild conditions. This suggests that cellular antioxidant defences might counteract the UVA-mediated photooxidation of DNA 6-TG at this intermediate step and ameliorate its biological effects. In agreement with this possibility, the antioxidant ascorbate protected DNA 6-TG against UVA oxidation and prevented the formation of GSO3. © The Author(s) 2009. Published by Oxford University Press.