| Abstrakt: |
Furan is a hepatic toxicant and carcinogen in rodents. Its microsomal metabolite, cis-2-butene-1,4-dial, is mutagenic in the Ames assay. Consistent with this observation, cis-2-butene-1,4-dial reacts with 2-deoxycytidine, 2-deoxyguanosine, and 2-deoxyadenosine to form diastereomeric adducts. HPLC analysis indicated that the rate of reaction with deoxyribonucleosides was dependent on pH. At pH 6.5, the relative reactivity was 2-deoxycytidine > 2-deoxyguanosine > 2-deoxyadenosine whereas it was 2-deoxyguanosine > 2-deoxycytidine > 2-deoxyadenosine at pH 8.0. Thymidine did not react with cis-2-butene-1,4-dial. The primary 2-deoxyguanosine and 2-deoxyadenosine reaction products were unstable and decomposed to secondary products. NMR and mass spectral analysis indicated that the initial 2-deoxyadenosine and 2-deoxyguanosine reaction products were hemiacetal forms of 3-(2-deoxy-β-d-erthyropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2 -al)-9H-imidazo[1,2-α]purine-9-one (structure 2) and 3-(2-deoxy-β-d-erythropentafuranosyl)-3,6,7,8-tetrahydro-7-(ethane-2 -al)-8-hydroxy-3H-imidazo[2,1-i]purine (structure 4), respectively. These adducts resulted from the addition of cis-2-butene-1,4-dial to the exo- and endocyclic nitrogens of 2-deoxyadenosine and 2-deoxyguanosine. The data provide support for the hypothesis that cis-2-butene-1,4-dial is an important genotoxic intermediate in furan-induced carcinogenesis. |
