Relationship between Mutagenicity of Heterocyclic Aromatic Amines and Stability of Their DNA Adducts: A Study by Semi-empirical Molecular Orbital Method

Quantitative structure-mutagenicity correlations were investigated for heterocyclic aromatic amines (HCAs) by use of a DNA model with three-base pairs. DNA adducts of thirteen HCAs were optimized by the PM3 method and energy decrease, ΔE, of each HCA due to formation of a DNA adduct was obtained as the stability of the adduct. The calculations for the HCA-DNA adducts revealed the interaction between HCA's methyl group and DNA's phosphate, which plays an important role in the stabilization of the adducts. The ΔE values plotted against the logarithm of HCA's mutagenicity, M, provided an almost straight line with the regression coefficient (R) of ?0.89 (R ²= 0.79). This good correlation suggests that binding reaction between HCA's nitrenium ion and DNA is an important rate-determining step in the metabolic transformation of HCAs.