Efficient nitroso group transfer from N-nitrosoindoles to nucleotides and 2'-deoxyguanosine at physiological pH. A new pathway for N-nitrosocompounds to exert genotoxicity.
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.
Lucas
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Biomonitoring and Molecular Interactions Section, MRC Toxicology Unit, Hodgkin Building, University of Leicester, P. O. Box 138, Lancaster Road, Leicester LE1 9HN, United Kingdom.
Gatehouse
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Shuker
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D000097:Acetonitriles / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003849:Deoxyguanosine / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000378:metabolism; D013058:Mass Spectrometry; D008956:Models, Chemical; D009603:Nitroso Compounds / Q000378:metabolism / Q000633:toxicity*; D009711:Nucleotides / Q000378:metabolism*
C119977:1-nitrosoindole-3-acetamide; C119978:1-nitrosoindole-3-acetic acid methyl ester; D000097:Acetonitriles; D007211:Indoles; D009603:Nitroso Compounds; D009711:Nucleotides; C053072:1-nitrosoindole-3-acetonitrile; D003849:Deoxyguanosine