Structural basis of the mutagenicity of heterocyclic amines formed during the cooking processes

Abstract

A data base consisting of 61 heterocyclic amines formed during food preparation and their des-amino analogs were subjected to structure-activity analysis using the CASE method, a structural activity relational expert system. The program identified the major structural determinants associated with mutagenic activity or lack thereof. The structures identified as contributing to the probability of activity as well as those associated with mutagenic potency were highly predictive of molecules not in the learning set. The major structural determinant, the aromatic amino moiety, and quantum mechanical calculations revealed that the mutagenic potency associated with this functionality derived from their contribution to the energy of the Lowest Unoccupied Molecular Orbital (LUMO).

Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes

“…Among the computed quantum mechanical factors, only the energy of the lowest unoccupied molecular orbital (LUMO) of the parent amines was strongly related to mutagenic potency, in agreement with earlier studies [Debnath et al, 1992;Zhang et al, 1993;Benigni et al, 19941. Figure 2 shows a plot of Log MP vs. the ab initio LUMO energies of the parent amines.…”

“…To improve our understanding of the genotoxic mechanisms of the AIAs and to predict the mutagenic activity of specific structures, quantitative structure-activity (QSAR) studies have been conducted by several groups [Hatch et al, 1991[Hatch et al, , 1992Sabbioni and Wild, 1992;Debnath et al, 1992;Ford and Griffin, 1992;Zhang et al, 1993; Benigni "Strain TA1538 (Knize et al, unpublished data). hStrain TA98 [Kaiser et al, 19861.…”

“…Substitution on the rings may block sites of detoxification reactions. Recent QSAR studies have included chemical fragment analysis and/or quantum mechanical calculations to help elucidate reaction mechanisms [Lewis, 1990;Zhang et al, 1993;Vikse et al, 19951.…”

Mutagenic potency of food-derived heterocyclic amines

“…A number of QSAR studies of the AIA food mutagens have found that high mutagenic potency is predicted by low-energy lowest unoccupied molecular orbital (LUMO) [12,13]. Our results show a reasonably strong correlation between LUMO energy and observed mutagenic potential of several heterocyclic amine mutagens (Figure 4).…”

SOS chromotest results in a broader context: Empirical relationships between genotoxic potency, mutagenic potency, and carcinogenic potency

“…that determine genotoxicity, mutagenicity and carcinogenicity [see Debnath et al, 1992a,b; Debnath and Hansch, 1992;Zhang et al, 1993; Hatch et al, 19921. Whether or not similar physical-chemical attributes are responsible for the genotoxicity, mutagenicity and carcinogenicity of the pure substances and complex mixtures listed in Appendices A and B remains to be determined.…”