Characterization of nucleoside adducts of cis-2-butene-1,4-dial, a reactive metabolite of furan.
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-beta-D-erthyropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2''-al)-9H-imidazo[1,2-alpha]purine-9-one (structure 2) and 3-(2'-deoxy-beta-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.
Byrns
Michael C
MC
Cancer Center and Division of Environmental and Occupational Health, School of Public Health, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA.
Predecki
Daniel P
DP
Peterson
Lisa A
LA
D000447:Aldehydes / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D018736:DNA Adducts / Q000737:chemistry*; D003839:Deoxyadenosines / Q000737:chemistry; D003849:Deoxyguanosine / Q000737:chemistry; D005663:Furans / Q000378:metabolism* / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry*; D051381:Rats; D013237:Stereoisomerism
D000447:Aldehydes; D002273:Carcinogens; D018736:DNA Adducts; D003839:Deoxyadenosines; D005663:Furans; D009705:Nucleosides; C015977:malealdehyde; D003849:Deoxyguanosine; C058118:2'-deoxyadenosine; C039281:furan