Mutational and DNA binding specificity of the carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline

作者：Solomon MS; Morgenthaler PML; Turesky RJ; Essigmann JM

来源：Journal of Biological Chemistry, 1996, 271(31): 18368-18374.

The mutagenic specificity of 2-amino3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a food-borne mutagen and carcinogen, was studied, Plasmid pK19 was modified by photolysis with the 2-azido form of the carcinogen, High pressure liquid chromatography confirmed that the photoactivated azide formed primarily C8 and N-2 guanyl adducts. Transformation of modified pK19 into excision repair competent Escherichia coli resulted in dose-dependent increases in genotoxicity and in mu tagenesis within the lacZ alpha target sequence. Upon induction of the SOS response, a 20-fold increase in mutation frequency over background was observed, A mutational spectrum for MeIQx, generated by sequencing 125 independent mutants, revealed base substitutions (41%), frameshifts (54%), and complex mutations (5.6%); >90% of the mutations occurred at G-C base pairs, Two hotspots were evident at runs of three or five G-C base pairs; similar to 60% of the mutations occurred at the hotspot sites, The hotspot at position 2532 produced mainly base substitutions, while that at position 2576 gave exclusively frameshift mutations, A polymerase inhibition assay mapped the sites of MeIQx adducts, Arrest sites were primarily at or one base 3' to a guanine residue, which correlated well with the distribution of mutations. No direct correlation was seen, however, between intensity of modification and hotspots for mutation.

• 出版日期1996-8-2