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Guanyl O⁶-Arylamination and O⁶-Arylation of DNA by the Carcinogen N-Hydroxy-1-naphthylamine¹

National Center for Toxicological Research, Jefferson, Arkansas 72079 [F. F. K.], and McArdie Laboratory for Cancer Research, University of Wisconsin Medical Center, Madison, Wisconsin 53706 [J. A. M., E. C. M.]

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 > polyguanylic acid > denatured DNA and ribosomal RNA > serum albumin > transfer RNA > 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-napththylamine. 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 H₂¹⁸O, 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.

¹ The research at the University of Wisconsin was supported by USPHS Grants CA-07175, CA-15785, and 5-T32-CA-09020.

² To whom requests for reprints should be addressed.

Received 5/ 1/78. Accepted 7/21/78.