Recent epidemiological studies have indicated that occupational exposure to the aromatic amine acetoaceto-o-toluidide (AAOT) was associated with a marked increase in urinary bladder cancers in Japan. However, little is known about the carcinogenicity of AAOT. To evaluate the urinary bladder carcinogenicity of AAOT, male and female F344 rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks followed by dietary administration of 0, 0.167, 0.5, or 1.5% AAOT for 31 weeks. The incidences and multiplicities of bladder tumors were significantly increased in the 0.5 and 1.5% groups of male and female rats in a dose-response manner. AAOT and seven downstream metabolites were detected in the urine of the male and female rats administered AAOT with levels increasing in a dose-dependent manner. The most abundant urinary metabolite of AAOT was the human bladder carcinogen o-toluidine (OTD), which was at least one order of magnitude higher than AAOT and the other AAOT metabolites. In a second experiment, male F344 rats were administered 0, 0.167, or 1.5% AAOT for 4 weeks. Gene expression analyses revealed that the expression of JUN and its downstream target genes was increased in the urothelium of male rats treated with 1.5% AAOT. These results demonstrate that AAOT promotes BBN-induced urinary bladder carcinogenesis in rats and suggest that overexpressed of JUN and its downstream target genes may be involved the bladder carcinogenicity of AAOT. In conclusion, AAOT, like other carcinogenic aromatic amines, is likely to be a carcinogen to the urinary bladder, and OTD metabolized from AAOT is the ultimate carcinogen.

最近的流行病学研究表明，在日本职业暴露于芳香胺乙酰乙酰邻甲苯胺（AAOT）与膀胱癌的明显增加有关。然而，关于AAOT的致癌性知之甚少。为了评估AAOT的膀胱致癌性，对雄性和雌性F344大鼠分别进行了N-丁基-N处理-（4-羟丁基）亚硝胺（BBN）持续4周，然后饮食中以0、0.167、0.5或1.5％AAOT的形式进行31周的饮食管理。在0.5％和1.5％的雄性和雌性大鼠组中，膀胱肿瘤的发生率和多重性以剂量反应方式显着增加。在AAOT雌雄大鼠的尿液中检测到AAOT和7种下游代谢产物，其水平呈剂量依赖性增加。AAOT最丰富的尿代谢产物是人类致癌物膀胱Ø-甲苯胺（OTD），比AAOT和其他AAOT代谢产物至少高一个数量级。在第二个实验中，对雄性F344大鼠进行0、0.167或1.5％AAOT的给药，持续4周。基因表达分析显示，在用1.5％AAOT处理的雄性大鼠的尿路上皮中，JUN及其下游靶基因的表达增加。这些结果表明AAOT促进了BBN诱导的大鼠膀胱癌的发生，并表明JUN及其下游靶基因的过表达可能与AAOT的膀胱癌有关。总之，AAOT与其他致癌芳香胺一样，很可能是膀胱的致癌物，而从AOT代谢的OTD是最终致癌物。