Photo-oxidation of 6-thioguanine by UVA: the formation of addition products with low molecular weight thiol compounds

Photochem Photobiol. Sep-Oct 2010;86(5):1038-45. doi: 10.1111/j.1751-1097.2010.00771.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / chemistry
  • Antimetabolites, Antineoplastic / radiation effects
  • Molecular Structure
  • Molecular Weight
  • Oxidation-Reduction
  • Thioguanine* / chemistry
  • Thioguanine* / radiation effects
  • Ultraviolet Rays*

Substances

  • Antimetabolites, Antineoplastic
  • Thioguanine