Selective reactivities of isocyanates towards DNA bases and genotoxicity of methylcarbamoylation of DNA.
The reactivities of methyl isocyanate (MIC) and phenyl isocyanate (PIC) with DNA, and the genotoxicity of MIC were investigated. MIC and PIC reacted with the exocyclic amino group of deoxycytidine, deoxyadenosine and deoxyguanosine to produce carbamoylated products. The reactions of both isocyanates with deoxycytidine were 2 and 4 orders of magnitude higher than with deoxyadenosine and deoxyguanosine, respectively. To explore the genotoxicity of MIC, M13mp9 RF DNA was modified with MIC and then introduced into E. coli. The plaque-forming efficiencies of DNA decreased with increasing dose levels, and the decreases were more pronounced in Uvr endonuclease-deficient strains (uvrA, uvrB and uvrC) than in the Uvr endonuclease-proficient strain, JM103. The differences in survival in JM103 and uvr- strains suggest that the methylcarbonyl adducts can be removed by the uvr excision-repair system. Modification of M13mp9 RF DNA with MIC induced MIC-dose-related, SOS-dependent mutations in the beta-galactosidase locus. These results demonstrate the genotoxic response of MIC-modified DNA in E. coli.
Tamura
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Department of Chemical Carcinogenesis, Michigan Cancer Foundation, Detroit 48201.
Aoki
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K
Lee
M S
MS
D002219:Carbamates; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003090:Coliphages; D003485:Cyanates / Q000378:metabolism / Q000633:toxicity*; D004269:DNA, Bacterial / Q000187:drug effects / Q000378:metabolism*; D004279:DNA, Viral; D003839:Deoxyadenosines / Q000378:metabolism; D003841:Deoxycytidine / Q000378:metabolism; D003849:Deoxyguanosine / Q000378:metabolism; D003853:Deoxyribonucleosides / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000378:metabolism; D004926:Escherichia coli; D017953:Isocyanates; D008745:Methylation; D009152:Mutagenicity Tests; D009153:Mutagens; D014162:Transfection
D002219:Carbamates; D003485:Cyanates; D004269:DNA, Bacterial; D004279:DNA, Viral; D003839:Deoxyadenosines; D003853:Deoxyribonucleosides; D015224:Dideoxynucleosides; D017953:Isocyanates; D009153:Mutagens; D003841:Deoxycytidine; C025319:phenyl isocyanate; C008461:methyl isocyanate; D003849:Deoxyguanosine