L. Cui, H. Sun, J. Wishnok
Nov 1, 2007
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0
Influential Citations
28
Citations
Quality indicators
Journal
Chemical research in toxicology
Abstract
Aromatic amines constitute one of the most extensively studied classes of chemical carcinogens. Although monocyclic aromatic amines are generally regarded as weak carcinogens, a recent epidemiologic study of bladder cancer found that the arylamine 3,5-dimethylaniline (3,5-DMA) may play a significant role in the etiology of this disease in man. Investigations using experimental animals also strongly suggested that DNA adducts-of indeterminate structure-formed by 3,5-DMA might account for its presumptive activity. The present study was undertaken to determine the structures of the major DNA adducts formed in vitro by the known, and possibly carcinogenic, N-hydroxylated metabolite. Calf thymus DNA (ct-DNA) was modified by reaction with N-acetoxy-3,5-dimethylaniline (N-AcO-3,5-DMA). After enzymatic hydrolysis of DNA to individual 2'-deoxyribonucleosides, adduct profiles were determined using HPLC/MS. 3,5-DMA formed four major DNA adducts, one to 2'-deoxyguanosine (dG), two to 2'-deoxyadenosine (dA), and one to 2'-deoxycytidine (dC). Reactions of N-AcO-3,5-DMA with dG, dA, and dC produced the same adducts as reaction with ct-DNA with very similar profiles. Adducts were isolated chromatographically and unambiguously characterized as N-(deoxyguanosin-8-yl)-3,5-dimethylaniline (dG-C8-3,5-DMA), 4-(deoxyadenosin- N(6)-yl)-3,5-dimethylaniline (dA- N(6)-3,5-DMA), N-(deoxyadenosin-8-yl)-3,5-dimethylaniline (dA-C8-3,5-DMA), and N-(deoxycytidin-5-yl)-3,5-dimethylaniline (dC-C5-3,5-DMA) by high-resolution mass spectra (HR-MS) and NMR spectroscopy including (1)H NMR, (13)C NMR, and two-dimensional NMR. This report includes the first detailed description of a dC adduct of an aromatic amine. The present results provide chemical support for a carcinogenic mechanism of action by 3,5-DMA based on N-hydroxylation and the intermediacy of a nitrenium ion in the formation of DNA adducts.