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.

In vitro deacetylation studies with isomeric acetamidobiphenyls using selective carboxylesterase inhibitors.

The hydrolysis of three isomeric arylamides 2-acetamidobiphenyl (2-AABP), 3-acetamidobiphenyl (3-AABP) and 4-acetamidobiphenyl (4-AABP) by microsomal carboxylesterases from mouse, hamster, guinea-pig, rat and rabbit livers was investigated. 2-AABP was hydrolysed at the fastest rate in all species except the mouse, the rate of hydrolysis of the 3 and 4 isomers was similar. The hydrolysis of the isomers in all species was inhibited by 10(-4) M paraoxon permitting the general identification of enzyme(s) responsible as "B" esterases. The more selective inhibitors bis-(4-nitrophenyl) phosphate (BNPP) and bis-(4-cyanophenyl) phosphate (BCPP) permitted further characterisation of the esterase(s) as a ES-3 carboxylesterase. However, the hydrolysis of 2-AABP was considerably less sensitive to these inhibitors than 3-AABP and 4-AABP, indicating that 2-AABP is a favoured substrate for the enzyme. The mouse arylamide hydrolysing activity was uniformly less sensitive to both BNPP and BCPP suggesting an enzyme distinct from ES-3 carboxylesterase may be involved.

Microsomal deacetylation of isomeric acetamidobiphenyls.

In vitro rates of deacetylation were measured with carcinogenic and noncarcinogenic isomeric arylamides using microsomal preparations from guinea pig, hamster, rat, mouse, rabbit and dog. Following incubation at 37 degrees, the substrate and hydrolysis products were extracted into ether and the corresponding aromatic amine quantified by gas-liquid chromatography. The data show that rates of deacetylation were both species and isomer dependent. In general, the highest rate of deacetylation in microsomes from all species was recorded with 2-acetamidobiphenyl (2-AABP); however, the mouse uniquely deacetylated 4-acetamidobiphenyl (4-AABP) most rapidly. The meta isomer 3-acetamidobiphenyl (3-AABP) was deacetylated at an intermediate rate in all species investigated. The variability in the rates of deacetylation within species may reflect the heterogeneity of the deacetylase enzymes and may be an important factor in amine/amide carcinogenesis.