Modulation of DNA adduct formation by successive exposures of DNA to small and bulky chemical carcinogens.
The effect of a carcinogen-DNA adduct on the formation of a second adduct upon subsequent exposure to a second carcinogen was studied using (i) a modified Maxam-Gilbert chemical sequencing reaction and (ii) a DNA synthesis termination analysis. A DNA fragment of known sequence was reacted with micromolar concentrations of N-methyl-N-nitrosourea (MNU), (+)-r-7,t-8-dihydroxy-t-9,10- epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), N-acetoxy-2- acetylaminofluorene (N-acetoxy-AAF), or aflatoxin B1-8,9-epoxide (AFB1 epoxide) singly or in successive double reactions. N-Acetoxy-AAF adducts were sensitive to the Maxam-Gilbert sequencing reaction for guanine; these adducts significantly blocked the formation of BPDE-guanine adducts. Treatment of DNA with BPDE, however, did not inhibit subsequent formation of N-acetoxy-AAF adducts. DNA synthesis termination analysis suggested that methylation of guanine altered subsequent arylation of guanine by N-acetoxy-AAF and AFB1 epoxide, and that combined treatment inhibited replication, an effect not seen after MNU treatment alone. Possible mechanisms for the modulation of carcinogen binding are discussed. It is concluded that not only is DNA damage by genotoxic carcinogens dependent upon both the chemical nature of the carcinogens and the nearest neighbors to target guanine bases, but that the effect of subsequent exposures to carcinogens is not always additive.
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Department of Community and Environmental Medicine, University of California at Irvine 92717-1825, USA.
Ross
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Salib
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Shank
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D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity; D000099:Acetoxyacetylaminofluorene / Q000633:toxicity; D016604:Aflatoxin B1 / Q000031:analogs & derivatives / Q000633:toxicity; D017104:Bacteriophage M13 / Q000235:genetics; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000187:drug effects; D018736:DNA Adducts; D017931:DNA Primers; D008770:Methylnitrosourea / Q000633:toxicity; D008969:Molecular Sequence Data
D002273:Carcinogens; D018736:DNA Adducts; D017931:DNA Primers; C006426:aflatoxin B1-2,3-oxide; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D000099:Acetoxyacetylaminofluorene; D008770:Methylnitrosourea; D004247:DNA; D016604:Aflatoxin B1