title: Photo-oxidation of 6-thioguanine by UVA: the formation of addition products with low molecular weight thiol compounds.
abstract: The thiopurine, 6-thioguanine (6-TG) is present in the DNA of patients treated with the immunosuppressant and anticancer drugs azathioprine or mercaptopurine. The skin of these patients is selectively sensitive to UVA radiation-which comprises >90% of the UV light in incident sunlight-and they suffer high rates of skin cancer. UVA irradiation of DNA 6-TG produces DNA lesions that may contribute to the development of cancer. Antioxidants can protect 6-TG against UVA but 6-TG oxidation products may undergo further reactions. We characterize some of these reactions and show that addition products are formed between UVA-irradiated 6-TG and N-acetylcysteine and other low molecular weight thiol compounds including β-mercaptoethanol, cysteine and the cysteine-containing tripeptide glutathione (GSH). GSH is also adducted to 6-TG-containing oligodeoxynucleotides in an oxygen- and UVA-dependent nucleophilic displacement reaction that involves an intermediate oxidized 6-TG, guanine sulfonate (G(SO3) ). These photochemical reactions of 6-TG, particularly the formation of a covalent oligodeoxynucleotide-GSH complex, suggest that crosslinking of proteins or low molecular weight thiol compounds to DNA may be a previously unrecognized hazard in sunlight-exposed cells of thiopurine-treated patients.
authors.affiliation: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts, UK.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Ren
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Xu
authors.forename: Peter
authors.initials: P
authors.lastname: Karran
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000528:radiation effects; D015394:Molecular Structure; D008970:Molecular Weight; D010084:Oxidation-Reduction; D013866:Thioguanine / Q000737:chemistry / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D000964:Antimetabolites, Antineoplastic; D013866:Thioguanine