Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity

The mutagenic/carcinogenic heterocyclic amines formed during the cooking of protein foods have been determined to be a potential risk to human health. Therefore, mitigation measures are beginning to be studied. A recent findi ng is that the induction of mutation in Salmonella by these amines can be i nhibited by the addition of flavonoids to the assay. This study combines da ta on the inhibitory process with structural, ab initio quantum chemical, h ydropathic, and antioxidant factors to develop a quantitative structure act ivity relationship (QSAR) database and statistical analysis. For 39 diverse flavonoids the inhibitory potency varied approximately 100-fold. Three pre dictive variables, in order of decreasing contribution to variance, are: (1 ) a large dipole moment; (2) after geometric minimization of energy, a smal l departure from planarity (i.e., small dihedral angle between the benzopyr an nucleus and the attached phenyl ring), and a low rotational energy barri er to achieving planarity; and (3) fewer hydroxyl groups on the phenyl ring . However, these variables account for less than half of the variance in in hibitory potency of the flavonoids. Frontier orbital energies and antioxida nt or radical scavenging properties showed little or no relationship to pot ency. We conclude that interference by the flavonoids with cytochrome P450 activation of the promutagens is the probable mechanism for inhibition of m utagenesis, and suggest avenues for further research. Published 2000 Wiley- Liss, Inc.(dagger)