o-Anisidine Dimer, 2-Methoxy-N4-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis
o-Anisidine Dimer, 2-Methoxy-N4-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis
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DOI：
10.1021/acs.chemrestox.0c00536
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发表时间：
2021-02-15
影响因子：
4.1
通讯作者：
Miyoshi, Noriyuki
中科院分区：
文献类型：
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作者：
Kobayashi, Takuma;Toyoda, Takeshi;Miyoshi, Noriyuki
单环芳香胺，邻甲苯胺（o-Tol）及其结构类似物邻茴香胺（o-Ans），分别是IARC第1组和第2A组膀胱致癌物，并参与代谢活化和DNA损伤。我们最近的研究表明，在o-Tol与S9混合物的体外反应和o-Tol暴露大鼠的体内尿液样本中检测到并鉴定出2-甲基-N-4-（2-甲基苯基）苯-1，4-二胺（MMBD），这是o-Tol的对-半脒型同源二聚体。据报道，MMBD具有强致突变性、遗传毒性和细胞毒性，表明其参与膀胱癌的发生。然而，o-Ans是否以与o-Tol类似的方式转化为活性代谢物以诱导DNA损伤仍然是未知的。在这项研究中，我们报告了一种新的o-Ans代谢物，2-甲氧基-N-4-（2-甲氧基苯基）苯-1，4-二胺（MxMxBD），一个二聚体通过头到尾结合（p-半脒形式），是首次在o-Ans暴露大鼠尿液中鉴定。与o-Ans相比，MxMxBD在N-乙酰转移酶过表达的鼠伤寒沙门氏菌菌株中诱导更强的致突变性，并在人膀胱癌T24细胞中诱导更强的遗传毒性和细胞毒性。这些结果表明，MxMxBD可能在一定程度上有助于膀胱癌的发生。除同源二聚化（如MxMxBD）外，在S9混合物的体外反应中，当o-Ans与o-Tol或苯胺（Ani）共孵育时，观察到异源二聚化。这项研究强调了重要的考虑因素的同二聚体和杂二聚体的单环芳香胺，包括o-Ans，o-Tol，和Ani，在膀胱癌发生的联合暴露风险的评估。
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-N-4-(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-N-4-(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.