DNA Adduct Formation by 2,6-Dimethyl-, 3,5-Dimethyl-, and 3-Ethylaniline in Vivo in Mice
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- 作者：Paul L. Skipper ; Laura J. Trudel ; Thomas W. Kensler ; John D. Groopman ; Patricia A. Egner ; Rosa G. Liberman ; Gerald N. Wogan ; Steven R. Tannenbaum
- 刊名：Chemical Research in Toxicology
- 出版年：2006
- 出版时间：August 2006
- 年：2006
- 卷：19
- 期：8
- 页码：1086 - 1090
- 全文大小：59K
- 年卷期：v.19,no.8(August 2006)
- ISSN：1520-5010
文摘
Aromatic amines such as 2-naphthylamine and 4-aminobiphenyl are established human bladdercarcinogens. Experimental evidence for carcinogenicity of monocylic aromatic amines is limited mostlyto 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 thisdisease in man. The present work was undertaken to test whether a genotoxic mechanism can accountfor the presumptive activity of 2,6-DMA, 3,5-DMA, and 3-EA by quantifying the binding of thesecompounds to DNA in vivo. Each of these three [14C]alkylanilines was administered at approximately100 
g/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 isolatedfrom each tissue. Adduct levels were determined by quantifying bound isotope using accelerator massspectrometry. Adducts were detectable in the bladder and liver DNA samples from every animal at everytime point at levels that ranged from 3 per 109 to 1.5 per 107 nucleotides. Adduct levels were highest inanimals given 3,5-DMA and lowest in those given 3-EA. Levels in both bladder and liver declined byseveralfold over the course of the experiment. Adducts were detected less frequently in the other fourtissues. Taken together, the results strongly suggest that these three alkylanilines are metabolized in vivoto electrophilic intermediates that covalently bind to DNA and that adducts are formed in the DNA ofbladder, which is a putative target organ for these alkylanilines.
g/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 isolatedfrom each tissue. Adduct levels were determined by quantifying bound isotope using accelerator massspectrometry. Adducts were detectable in the bladder and liver DNA samples from every animal at everytime point at levels that ranged from 3 per 109 to 1.5 per 107 nucleotides. Adduct levels were highest inanimals given 3,5-DMA and lowest in those given 3-EA. Levels in both bladder and liver declined byseveralfold over the course of the experiment. Adducts were detected less frequently in the other fourtissues. Taken together, the results strongly suggest that these three alkylanilines are metabolized in vivoto electrophilic intermediates that covalently bind to DNA and that adducts are formed in the DNA ofbladder, which is a putative target organ for these alkylanilines.