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.
The effect of insulin-dependent diabetes on the hepatic microsomal activation of chemical carcinogens to mutagenic intermediates in the Ames test was investigated in rats pretreated with streptozotocin. In order to discern between the effects of streptozotocin itself and that of the resulting diabetes, groups of streptozotocin-treated rats received either nicotinamide simultaneously with the diabetogenic agent to prevent the onset of diabetes or daily treatment with insulin in order to antagonise the effects of diabetes. The activation of two nitrosamines, nitrosopiperidine and nitrosopyrrolidine was markedly increased following treatment of the animals with streptozotocin, the effect being preventable by nicotinamide and effectively antagonised by insulin. A similar increase in mutagenic response was also seen when Glu-P-1, a carcinogen generated during the cooking of proteinaceous food, was employed as the mutagen. In contrast, the diabetic rats were less efficient than control animals in activating the aromatic amine 2-aminofluorene to mutagenic intermediates. Concomitant administration of nicotinamide with streptozotocin prevented the decrease in mutagenicity, and daily treatment of diabetic rats with insulin partially restored mutagenic response to control levels. Streptozotocin-induced diabetes had no effect on the mutagenicity of 4-aminobiphenyl and the two polycyclic aromatic hydrocarbons, benzo(a)pyrene and 3-methylcholanthrene. The present findings clearly illustrate that diabetes modulates the metabolic activation of carcinogenic chemicals, the effect being dependent on the nature of the carcinogen.
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