o-Anisidine Dimer, 2-Methoxy-N4-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis.

Abstract

Monocyclic aromatic amines, o-toluidine (o-Tol) and its structural analog o-anisidine (o-Ans), are IARC Group 1 and Group 2A urinary bladder carcinogens, respectively, and are involved in metabolic activation and DNA damage. Our recent study revealed that 2-methyl-N4-(2-methylphenyl) benzene-1,4-diamine (MMBD), a p-semidine-type homodimer of o-Tol, was detected and identified in an in vitro reaction of o-Tol with S9 mix and in vivo urinary samples of o-Tol-exposed rats. Potent mutagenic, genotoxic, and cytotoxic activities were reported with MMBD, suggesting its involvement in urinary bladder carcinogenesis. However, it remains unknown whether o-Ans is converted to active metabolites to induce DNA damage in a similar manner as o-Tol. In this study, we report that a novel o-Ans metabolite, 2-methoxy-N4-(2-methoxyphenyl) benzene-1,4-diamine (MxMxBD), a dimer by head-to-tail binding (p-semidine form), was for the first time identified in o-Ans-exposed rat urine. MxMxBD induced a stronger mutagenicity in N-acetyltransferase overexpressed Salmonella typhimurium strains and potent genotoxicity and cytotoxicity in human bladder carcinoma T24 cells compared with o-Ans. These results suggest that MxMxBD may to some extent contribute toward urinary bladder carcinogenesis. In addition to homodimerization, such as MxMxBD, heterodimerizations were observed when o-Ans was coincubated with o-Tol or aniline (Ani) in in vitro reactions with S9 mix. This study highlights the important consideration of homodimerizations and heterodimerizations of monocyclic aromatic amines, including o-Ans, o-Tol, and Ani, in the evaluation of the combined exposure risk of bladder carcinogenesis.

• Authors: Takuma Kobayashi, Takeshi Toyoda, Yuya Tajima, Shinji Kishimoto, Yuta Tsunematsu, Michio Sato, Kohei Matsushita, Takanori Yamada, Yuko Shimamura, Shuichi Masuda, Masako Ochiai, Kumiko Ogawa, Kenji Watanabe, Takeji Takamura-Enya, Yukari Totsuka, Keiji Wakabayashi, Noriyuki Miyoshi
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 34 Issue 3 Pg. 912-919 (03 15 2021) ISSN: 1520-5010 [Electronic] United States
• PMID: 33587850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens

Topics

• Animals
• Carcinogens (chemistry, toxicity)
• Male
• Molecular Structure
• Mutagenicity Tests
• Rats
• Rats, Inbred F344
• Urinary Bladder Neoplasms (chemically induced)