Efficient Nitroso Group Transfer fromN-Nitrosoindoles to Nucleotides and 2′-Deoxyguanosine at Physiological pH

• Published in: The Journal of biological chemistry 1999-06, Vol.274 (26), p.18319
• Main Authors: Lynda T. Lucas, David Gatehouse, David E. G. Shuker
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.26.18319

The endogenous formation of N -nitrosoindoles is of concern since humans are exposed to a variety of naturally occurring and synthetic indolic compounds. As part of a study to evaluate the genotoxicity of N -nitrosoindoles, the reactions of three model compounds with purine nucleotides and 2′-deoxyguanosine at physiological pH were investigated. The profiles of reaction products were identical for each of the N -nitrosoindoles and three distinct pathways of reaction could be discerned. These pathways were: (i) depurination to the corresponding purine bases, (ii) deamination, coupled with depurination, to give hypoxanthine and xanthine, and (iii) formation of the novel nucleotide 2′-deoxyoxanosine monophosphate and its corresponding depurination product oxanine in reactions with 2′-deoxyguanosine monophosphate. 2′-Deoxyoxanosine and oxanine were observed in reactions with 2′-deoxyguanosine. Further studies showed that formation of all of these products could be rationalized by an initial transnitrosation step. These results suggest that, in contrast to many other genotoxic N -nitrosocompounds which are known to alkylate DNA, the genotoxicity of N -nitrosoindoles is likely to arise through transfer of the nitroso group to nucleophilic sites on the purine bases. All of the products resulting from transnitrosation by N -nitrosoindoles are potentially mutagenic. These findings reveal a new pathway for N -nitrosocompounds to exert genotoxicity.