N2-amination of guanine to 2-hydrazinohypoxanthine, a novel in vivo nucleic acid modification produced by the hepatocarcinogen 2-nitropropane

2-Nitropropane, an industrial chemical and a hepatocarcinogen in rats, indu ces aryl sulfotransferase-mediated liver DNA and RNA base modifications [So duml R. S., Sohn, O. S., Nie, G;., and Fiala, E. S, (1994) Chem. Res. Toxic ol. 7, 344-351]. Two of these modifications were previously identified as 8 -aminoguanine and 8-oxoguanine. We now report that the base moiety of the s o far unidentified third nucleic acid modification? namely RX1 in RNA and D X1 in DNA, is 2-hydrazinohypoxanthine (N-2-aminoguanine). 2-Hydrazinoinosin e and 2-hydrazinodeoxyinosine, synthesized by adapting published procedures , cochromatographed with RX1 and DX1 of liver RNA and DNA, respectively, fr om 2-nitropropane-treated rats. 2-Hydrazinoinosine and 2-hydrazinodeoxyinos ine are unstable in solution like the in vivo products RX1 and DX1. At neut ral pH, hypoxanthine nucleoside is the major product of decomposition, whil e at pH 10 or above, xanthine nucleoside is also formed. RX1 and DX1 could be generated in the anaerobic reactions of hydroxylamine-O-sulfonic acid, a n intermediate in the proposed activation pathway of 2-nitropropane, with g uanine nucleosides. These results provide further evidence for the activati on of 2-nitropropane and other carcinogenic secondary nitroalkanes to a rea ctive species capable of aminating nucleic acids and proteins.