Guanyl O6-arylamination and O6-arylation of DNA by the carcinogen N-hydroxy-1-naphthylamine.
The carcinogen N-hydroxy-1-naphthylamine reacted with nucleic acids and protein under slightly acidic conditions (pH 5) to form covalently bound derivatives with 3 to 20 naphthyl residues/1000 monomer units. The level of binding was in the following order: DNA greater than polyguanylic acid greater than denatured DNA and ribosomal RNA greater than serum albumin greater than transfer RNA greater than polyadenylic acid. Reactions with nucleosides and nucleotides were not detected, and the binding of N-hydroxy-1-naphthylamine to DNA was not inhibited by the addition of nucleosides, nucleotides, methionine, or glutathione. The reaction rates were first order with respect to both DNA and N-hydroxy-1-naphthylamine concentrations. Enzymatic hydrolysis of the DNA containing naphthyl residues yielded 3 nucleoside-arylamine adducts. The major adduct was identified by chemical, ultraviolet, nuclear magnetic resonance, and mass spectrometric analyses as N-(deoxyguanosin-O6-yl)-1-naphthylamine. The other two adducts were identified as 2-(deoxyguanosin-O6-yl)-1-naphthylamine and its decomposition product. Direct evidence for acid-dependent arylnitrenium ion formation was obtained by isotope exchange upon solvolysis of N-hydroxy-1-naphthylamine in acidic H2 18O, and carbocation formation was indicated by the formation of the solvolysis products, 1-amino-2-naphthol and 1-amino-4-naphthol. These studies demonstrated the conversion of a carcinogenic N-hydroxy arylamine to electrophilic arylnitrenium ion and carbocation species that display high selectivity toward macromolecules. The roles of these electrophiles and their macromolecular adducts in the initiation of urinary bladder carcinogenesis through formation of promutagenic lesions in DNA are suggested.
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000586:Amination; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D006898:Hydroxylamines; D007700:Kinetics; D008956:Models, Chemical; D009281:Naphthalenes / Q000031:analogs & derivatives; D011506:Proteins / Q000378:metabolism
D006898:Hydroxylamines; D009281:Naphthalenes; D011506:Proteins; D004247:DNA; D015057:1-Naphthylamine; D003849:Deoxyguanosine