Aromatic
amines such as
2-naphthylamine and
4-aminobiphenyl are established human bladder
carcinogens. Experimental evidence for carcinogenicity of monocylic aromatic
amines is limited mostly to other organs, but a recent epidemiologic study of
bladder cancer found that 2,6-dimethyl- (2,6-DMA), 3,5-dimethyl- (3,5-DMA), and
3-ethylaniline (3-EA) may play a significant role in the etiology of this disease in man. The present work was undertaken to test whether a genotoxic mechanism can account for the presumptive activity of 2,6-DMA, 3,5-DMA, and 3-EA by quantifying the binding of these compounds to
DNA in vivo. Each of these three [(14)C]alkylanilines was administered at approximately 100 microg/kg to C57BL/6 mice, which were subsequently sacrificed 2, 4, 8, 16, and 24 h post-dosing. Bladder, colon, kidney, liver, lung, and pancreas were harvested from each animal, and
DNA was isolated from each tissue. Adduct levels were determined by quantifying bound
isotope using accelerator mass spectrometry. Adducts were detectable in the bladder and liver
DNA samples from every animal at every time point at levels that ranged from 3 per 10(9) to 1.5 per 10(7)
nucleotides. Adduct levels were highest in animals given 3,5-DMA and lowest in those given 3-EA. Levels in both bladder and liver declined by severalfold over the course of the experiment. Adducts were detected less frequently in the other four tissues. Taken together, the results strongly suggest that these three alkylanilines are metabolized in vivo to electrophilic intermediates that covalently bind to
DNA and that adducts are formed in the
DNA of bladder, which is a putative target organ for these alkylanilines.