DNA adduction by the potent carcinogen aflatoxin B1 : mechanistic studies

摘要: Aflatoxin B1, a potently carcinogenic fungal metabolite, is converted to the biologically active form by chemical oxidation using dimethyldioxirane and enzymatically cytochrome P450 mixed-function oxidases. Both processes give rise mixtures of exo- endo-8,9-epoxides. Methanolysis studies reveal exclusive trans opening both epoxides under neutral conditions in CH3OH CH3OH/H2O mixtures; an SN2 mechanism postulated. Under acidic conditions, exo isomer gives cis solvolysis products, suggesting that reaction is, at least part, SN1; endo only product. The reacts with DNA attack nitrogen atom 7 position guanine on C8 epoxide adduct; fails adduct this or any other site DNA. strongly mutagenic base-pair reversion assay employing Salmonella typhimurium; essentially nonmutagenic. B1 its derivatives intercalate These results are consistent which intercalation optimally orients for but places orientation precludes reaction. Thus, while potent mutagen, react