Comparison of CoMFA models for Salmonella typhimurium TA98, TA100, TA98+S9and TA100+S9 mutagenicity of nitroaromatics

Comparative Molecular Field Analysis (CoMFA) was applied to a comprehensive data set of heterogeneous nitroaromatics tested in Salmonella typhimurium TA98 and TA100 with and without S9 microsomal activation. The four CoMFA mo dels developed agree with postulated mechanisms of mutagenicity, and explai n over 70% of the corresponding mutagenic variance. The standard deviation coefficient contours common in the four models included high electronic den sity regions equivalent to C4-C5 in the pyrene ring, and an electron defici ent site equivalent to C6. These areas are associated with high mutagenicit y. Electron deficient areas may be related with the nitroreductive bioactiv ation of nitroaromatics. Electron rich sites may be involved with oxidative mechanisms analogous to the bioactivation pathway of polycyclic aromatic h ydrocarbons. The contribution of steric factors to mutagenicity follows the order TA98 + S9 > TA98 > TA100 + S9 > TA100. The models indicated that inc reasing bulk perpendicular to the aromatic plane would decrease mutagenicit y, but increasing the aromatic ring system along a region corresponding to C6-C7 in I-nitropyrene would increase mutagenicity.