Substituent effects on the in vitro and in vivo genotoxicity of 4-aminobiphenyl and 4-aminostilbene derivatives

4-Amino-4'-substituted biphenyls and 4-aminostilbenes substituted in the 3' or 4' position were studied for their in vitro and in vivo genotoxicity. The in vitro mutagenicity of the biphenyls with and without S9 activation was established with Salmonella strains TA98 and TA100 and that of the stilbenes with the same strains plus TA98/1,8-DNP6. The in vivo genotoxicity assay with both series of compounds was for chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of the chemicals. Hammett values of substituents, partition coefficients and frontier orbital energies (ELUMO and EHOMO) of the compounds were used for correlations with mutagenicity. The Salmonella mutagenicity in TA98 and TA98/1,8-DNP6 with S9 was correlated to Hammett [sigma]+ values for the 4-aminostilbene substituents, showing a strong trend of increasing mutagenicity with an increase in the electron-withdrawing capability of the substituent. Hydrophobicity of the stilbenes, however, had little effect on their relative mutagenicity. The 4-aminobiphenyls showed a correlation between their mutagenicity and Hammett [sigma]+ values of their 4'-substituents in stain TA98 with S9, although the trend was not as strong as for the stilbenes. But unlike the stilbenes, TA98 mutagenicity of the biphenyls could also be correlated to hydrophobicity, and structure-activity correlations for the biphenyls was substantially improved when both [sigma]+ and hydrophobicity data were included. For strain TA100 with S9, little correlation was found between mutagenicity of the stilbenes and any of, the parameters. However, a limited correlation did exist between the mutagenicity of the biphenyls and their hydrophobicity. There was also limited correlations of the mutagenicity for the stilbenes in TA98 and TA98/1,8-DNP6 with S9 to ELUMO or EHOMO. The in vivo genotoxicity results for the biphenyls and stilbenes could not be correlated to electronic effects as for the in vitro results, nor could they be explained by hydrophobicity. However, it is interesting to note that 3'-substituted 4-aminostilbenes were all substantially more genotoxic in vivo than their corresponding 4'-substituted counterparts. The most genotoxic compound in vivo in either series was 4-aminostilbene which would not have been predicted from the in vitro results.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31865/1/0000815.pd

ortho-Substituent effects on the in vitro and in vivo genotoxicity of benzidine derivatives

Benzidine and its 3,3'-diamino, 3,3'-dimethyl, 3,3'-dimethoxy, 3,3'-difluoro, 3,3'-dichloro, 3,3'-dibromo, 3,3'-dicarbomethoxy and 3,3'-dinitro derivatives together with 2-nitrobenzidine and 3-nitrobenzidine were compared for their in vitro and in vivo genotoxicity. Relative mutagenicity was established with Salmonella strains TA98, TA98/1,8-DNP6 and TA100 with and without S9 activation. All the derivatives in the presence of S9 were more mutagenic than benzidine with 3,3'-dinitro- and 3-nitro-benzidine having the greatest mutagenicity. Mutagenicity in all 3 strains with S9 activation could be correlated to electron-withdrawing ability of substituent groups, as measured by the basicity of the amines. This correlation was explained on the basis that electron-withdrawing groups could favor the stability of the mutagenic intermediate N-hydroxylamine and also enhance the reactivity of the ultimate mutagenic species, the nitrenium ion. Mutagenicity was also correlated to the energy of the lowest unoccupied molecular orbitals (ELUMO). Hydrophobicity was found to have very limited effect on the relative mutagenicity of our benzidine derivatives. The in vivo endpoint was chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of benzidine and its derivatives. In contrast to the in vitro results, while all the amines were genotoxic in vivo, only the 3-nitro derivative had a significant increase in toxicity over benzidine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30582/1/0000219.pd