Novel o-Toluidine Metabolite in Rat Urine Associated with Urinary Bladder Carcinogenesis
| Autor: | Keiji Wakabayashi, Yukari Totsuka, Yuichiro Hirayama, Kumiko Ogawa, Takeji Takamura-Enya, Takeshi Toyoda, Kohei Matsushita, Yuya Tajima, Takanori Yamada, Kenji Watanabe, Noriyuki Miyoshi |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences DNA damage organic chemicals Metabolite Aromatic amine General Medicine 010501 environmental sciences Toxicology 01 natural sciences Molecular biology Adduct 03 medical and health sciences chemistry.chemical_compound Enzyme chemistry DNA adduct bacteria Carcinogen DNA 030304 developmental biology 0105 earth and related environmental sciences |
| Zdroj: | Chemical Research in Toxicology. 33:1907-1914 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/acs.chemrestox.0c00098 |
| Popis: | o-Toluidine (o-Tol), a monocyclic aromatic amine, causes bladder cancer in humans and experimental animals and is therefore classified as a Group 1 carcinogen (IARC) in which the carcinogenicity of o-Tol is involved in metabolic activation, DNA damage, and DNA adduct formation. In the DNA adduct formation mechanism, o-Tol is metabolized by N-hydroxylation, N-acetoxylation, and then deacetoxylation to produce an electrophilic nitrenium ion, which is able to bind to a DNA base, such as dG-C8. Therefore, dG-C8-o-Tol is thought to be a plausible DNA adduct of o-Tol exposure. However, direct detection of dG-C8-o-Tol in biological samples has not been reported yet. Here, we show that a novel o-Tol metabolite, 2-methyl-N1-(2-methylphenyl)benzene-1,4-diamine (MMBD), a dimer by head-to-tail binding, was identified for the first time in o-Tol-exposed rat urine. MMBD was also detected in a reaction of o-Tol and S9 mix, indicating the formation was catalyzed by an enzymatic reaction. Moreover, MMBD showed a potent stronger mutagenicity in N-acetyltransferase overexpressed Salmonella typhimurium strains,and cytotoxicity in human bladder carcinoma T24 cells and human spleen lymphoblastoid TK6 cells compared with o-Tol. Furthermore, a DNA adduct (m/z 478.1) corresponding to dG-MMBD was detected in the reaction of calf thymus DNA with rat urine containing MMBD, and also in hepatic DNA of rats treated with o-Tol. These results therefore suggested that o-Tol-induced bladder carcinogenesis could be at least partly attributed to MMBD formation. The possible dimerization of monocyclic aromatic amines should be considered in the evaluation of the risk of bladder carcinogenesis after exposure. |
| Databáze: | OpenAIRE |
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