Acetoaceto-o-Toluidide Enhances Cellular Proliferative Activity in the Urinary Bladder of Rats
Acetoaceto-o-Toluidide Enhances Cellular Proliferative Activity in the Urinary Bladder of Rats
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DOI：
10.1093/toxsci/kfz051
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发表时间：
2019-06-01
影响因子：
3.8
通讯作者：
Wanibuchi, Hideki
中科院分区：
文献类型：
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作者：
Okuno, Takahiro;Gi, Min;Wanibuchi, Hideki
乙酰乙酰邻甲苯胺 (AAOT) 由邻甲苯胺 (OTD) 制成，用于合成颜料。最近发表了一份关于长期接触 OTD 和 AAOT 的日本工人职业性膀胱癌的报告。 OTD是众所周知的人类膀胱致癌物；然而，人们对AAOT的毒性和致癌性知之甚少。本研究的目的是评估 AAOT 对膀胱上皮的毒性作用。在体外，在大鼠 (MYP3) 和人 (1T1) 尿路上皮细胞中评估了 AAOT 和 OTD 的细胞毒性。在 MYP 细胞和 1T1 细胞中，AAOT 的 LC50 均高于 OTD。在体内，给 6 周大的雄性和雌性 F344 大鼠喂食补充有 0%、1.5% 或 3% AAOT 的饮食 4 周。在给予 AAOT 的雄性和雌性大鼠的膀胱尿路上皮中，单纯性增生、细胞增殖活性和 γ-H2AX 表达（预测致癌性的新标志物）的发生率以剂量依赖性方式显着增加。此外，在施用 AAOT 的雄性和雌性大鼠中，AAOT 的主要尿液代谢物是 OTD。这些结果表明 AAOT 具有增殖增强活性，并表明 AAOT 代谢的 OTD 可能在 AAOT 对大鼠的有害作用中发挥关键作用。本研究结果还表明，AAOT与其他致癌芳香胺一样，很可能是人类膀胱致癌物。
Acetoaceto-o-toluidide (AAOT) is made from ortho-toluidine (OTD) and is used for the synthesis of pigments. A report of occupational urinary bladder carcinomas in Japanese workers chronically exposed to OTD and AAOT has recently been published. OTD is a well-known human urinary bladder carcinogen; however, little is known about the toxicity and the carcinogenicity of AAOT. The aim of the present study is to evaluate the toxic effects of AAOT on urinary bladder epithelium. In vitro, the cytotoxicities of AAOT and OTD were evaluated in rat (MYP3) and human (1T1) urothelial cells. The LC50 of AAOT was higher than that of OTD in both MYP cells and 1T1 cells. In vivo, 6-week-old male and female F344 rats were fed diets supplemented with 0%, 1.5%, or 3% AAOT for 4 weeks. Incidences of simple hyperplasia, cell proliferative activity, and gamma-H2AX expression, which is a novel marker for the prediction of carcinogenicity, were significantly increased in a dose-dependent manner in the bladder urothelium of male and female rats administered AAOT. Furthermore, in male and female rats administered AAOT, the major urine metabolite of AAOT was OTD. These results demonstrate that AAOT has proliferation-enhancing activity and suggest that OTD metabolized from AAOT may play a pivotal role in the deleterious effects of AAOT in rats. The results of the present study also indicate that AAOT, like other carcinogenic aromatic amines, is likely to be a human bladder carcinogen.