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1F - QSAR (TUP/51) Identification of the structural requirements for mutagencitiy: II. Discriminating electrophilic and frameshift mechanisms of mutagenicity. Mekenyan, Ovanes1, Serafimova, Rossitsa1, Thompson, Ed2, 1 Laboratory of Mathematical Chemistry, University “Prof. As. Zlatarov”, Bourgas, Bulgaria, Bulgaria2 Human & Environ. Safety, The Procter & Gamble Company, MVL, Cincinnati, OH 45239-8707 ABSTRACT- COREPA approach has been used to discriminate electrophilic and frameshift mutagenicity. For that purpose, training sets were constructed with NTP chemicals eliciting predominantly each of these mechanisms of mutagenicity; chemicals with high activity against TA100 and TA98 were classified as electrophilic and frameshift mutagens, respectively. The electrophilic model of mutagenicity was found to consist of alerting groups associated with so called secondary electrophiles, i.e., chemicals having highly reactive groups that get metabolized, thus producing very active electrophilic sites. The rate limiting interaction is formation of highly reactive electrophilic sites that subsequently participate in electrophilic addition (AdE1) or substitution (SE1) reactions causing eventually mutagenicity. For electrophilic mutagens the electrophilic mechanism of interaction is predominant with a subsequent covalent bond rearrangement. The alerting groups in frameshift mutagens are also electrophilic sites that, however, have less pronounced electrophilicty than the sites produced by activation of reactive fragments in electrophilic mutagens. The interactions are based on electrophilicity of parent chemicals without activation step. These interactions could be classified as second order (bimolecular) processes of electrophilic addition (AdE2) or substitution (SE2). The electrophilic sites in frameshift mutagens interact with DNA by weak interactions. A multitude of DNA bases could be attacked, which eventually explains the violation of their frame. In both mutagenicity models the requirements for alerting groups are combined with global electronic requirements that fire these reactive groups. For frameshift mutagens Egap is the parameter combined with alerting groups, whereas for electrophilic mutagens the predominantly combined global parameter is electronegativity. The results are in agreement with the observed requirement for higher electrophilicity of chemicals eliciting electrophilic mutagenicity. The largest difference between both models is the appearance of global geometric parameters in the requirements for frameshift mutagenicity, which is in accordance with possible intercalation character of underlying mechanism. Key words: frameshifts, mutagenicity mechanisms, electrophiles |
