Quantum chemical studies of aflatoxins: Metabolism and carcinogenic activity

Specific electronic properties related to the metabolic transformation and adduct formation with DNA were calculated for a series of five aflatoxins, AFB1, AFG1, AFP1, AFM1, and aflatoxicol (AFL), as well as for two precursors of AFB1, versicolorin A and sterigmatocystin. The aim of this study was to investigate to what extent such electronic parameters determine relative apparent mutagenic and carcinogenic activities of these compounds. Using two semiempirical all-valence electron methods, IEHT and INDO, the results obtained indicated that for all these compounds the 2,3-vinyl ether double bond is highly susceptible to epoxidation, and this susceptibility is independent of the remaining ring structure and substituents. Further, the epoxides in turn readily form highly electrophilic carbocations whose stability and reactivity are not significantly influenced by chemical structure changes among the seven analogs studied. The results also suggest that major detoxification pathways mitigated by cytochrome P450 metabolism are not likely. Thus differences in potencies do not appear to be caused by differences in electronic properties related to the metabolic transformation and adduct formation, and could be the result of other properties such as lipophilicity and steric effects on enzyme activity.