A rationale for the non-mutagenicity of 2- and 3-aminobiphenyls

Of the three isomeric forms of aminobiphenyl, only 4-aminobiphenyl is an established carcinogen while the 2-isomer is considered as a non-carcinogen and 3-aminobiphenyl is at best described as a weak carcinogen. In the present studies we investigated the mutagenicity of these three compounds, their N-hydroxy derivatives and their nitrosoderivatives in the Ames test using the Salmonella typhimurium strains TA98 and TA100. The studies were performed both in the absence and presence of an activation system derived from the liver of rats pretreated with Aroclor 1254. Of the three isomers only 4-aminobiphenyl exhibited mutagenicity and only in the presence of an activation system. N-Hydroxy-4-aminobiphenyl was a potent direct mutagen in both bacterial strains, N-hydroxy-2-aminobiphenyl was mutagenic in only TA100 while N-hydroxy-3-aminobiphenyl displayed mutagenicity in neither strain. Both 2- and 3-nitrosobiphenyls were direct mutagens in strain TA100. These findings suggest that the weak carcinogenicity of 3-aminobiphenyl may be attributed to the lack of genotoxicity of its N-hydroxyderivative, whereas in the case of 2-aminobiphenyl it may be due to the inability of the hepatic preparations to catalyse its N-hydroxylation, which is in agreement with published in vivo metabolic studies. It is interesting that of the three isomers only 2-aminobiphenyl is non-planar, forming a dihedral angle of 40 degrees, and this may preclude it from acting as a substrate of the P-450I family of haemoproteins, which selectively catalyses the N-hydroxylation of many aromatic amines including 4-aminobiphenyl.