In vitro reaction of the carcinogen, N-hydroxy-2-naphthylamine, with DNA at the C-8 and N2 atoms of guanine and at the N6 atom of adenine

Abstract

The probable ultimate urinary bladder carcinogen, N-hydroxy-2-naphthylamine (N-HO-2-NA), reacted with nucleic acids and proteins under mildly acidic conditions (pH 5) to form covalently bound derivatives. The extent of reaction was in the order: polyguanylic acid > DNA > or = protein > rRNA > tRNA > polyadenylic acid, polyuridylic acid > polycytidylic acid. At pH 7, appreciable reaction occurred only with protein. Enzymatic hydrolyses of the DNA, which contained 1.5 naphthyl residues/1000 nucleotides, yielded 3 nucleoside-arylamine adducts. From chemical, u.v., n.m.r., and mass spectrometric analyses, the adducts were identified as 1-(deoxyguanosin-N2-yl)-2-naphthylamine, 1-(deoxyadenosin-N6-yl)-2-naphthylamine, and a purine ring-opened derivative of N-(deoxyguanosin-8-yl)-2-naphthylamine, tentatively identified as 1-[5-(2,6-diamino-4-oxopyrimidinyl-N6-deoxyriboside)]-3-(2-naphthyl)urea. The properties of these adducts and their possible role in the initiation of carcinogenesis are discussed.