STUDY OF EXPERIMENTAL PATHOLOGY CONCERNING TO CARCINOGENICITY OF ARSENIC BASED ON THE METABOLISM OF INORGANIC ARSENIC

基于无机砷代谢的砷致癌实验病理学研究

• 批准号: 10670215
• 负责人: WANIBUCHI Hideki
• 金额: $ 1.98万
• 依托单位: Osaka City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670215/
• 关键词: 8-OHdG; ODC transgenic mice; carcinogenicity; arsenic; DMA; cell proliferation; bladder cancer; skin carcinogenesis; P53ノックアウトマウス; dimethylarsinic acid; monomethylarsonic acid; thrimethylarsine oxide; 細胞増殖; 80HdG; 無機ヒ素; dimethylarsinie acid

Although numerous epidemiological findings have indicated that arsenics are associated with increased incidences of lung, skin, liver, and bladder cancers, experimental data from animal models to support the hypothesis of carcinogenic effects are limited. Dimethylarsinic acid (DMA) is a major form of organic arsenic in the environment. In addition, it is a major metabolite of ingested inorganic arsenics in most animals. Male F344/DuCrj rats were administered 12.5, 50, or 200 ppm of DMA in the drinking water for 104 weeks, urinary bladder tumors were observed in 0 of 33,8 of 31, and 12 of 31 animals, respectively. No bladder tumors developed in the controls. These results indicate that DMA is carcinogenic for the rat urinary bladder. Promotion effect of DMA on skin carcinogenesis in K6/ODC transgenic mice were tested. DMA showed promoting effect on skin tumorigenesis in k6/ODC transgenic mice as well as TPA.DMA treatment in NBR rats revealed the elevation of 8-OHdG formation in the kidney . PCNA positive-cells were increased in the rats kidney tissue treated with DMA.Inorganic arsenics (arsenite and arsenate) are metabolized to monomethylarsonic acid (MMA), DMA, and trimethylarsine oxide (TMAO) in most mammals. Promoting effects of sodium arsenite and these related organic arsenics (MMA, DMA, TMAO) in a rat submultiorgan-carcinogenesis test were therefore investigated. With regard to bladder carcinogenesis, DMA most-strongly enhanced the tumor induction, followed in decreasing order by MMA and TMAO, whereas AsBe and NaAsIII did not. The enhancement of bladder carcinogenesis was correlated with production of one unknown urinary metabolite of arsenics. These results revealed that MMA and TMAO have carcinogenic potential, as well as DMA.

虽然许多流行病学研究结果表明，砷与肺癌，皮肤癌，肝癌和膀胱癌的发病率增加，动物模型的实验数据，以支持致癌作用的假设是有限的。二甲基胂酸（DMA）是环境中有机砷的主要存在形式。此外，它是大多数动物摄入无机砷的主要代谢物。雄性F344/DuCrj大鼠饮用含12.5、50和200 ppm DMA的饮水104周后，分别在0/33、8/31和12/31只动物中观察到膀胱肿瘤。对照组中未发生膀胱肿瘤。这些结果表明DMA对大鼠膀胱具有致癌性。检测DMA对K6/ODC转基因小鼠皮肤癌变的促进作用。DMA对k6/ODC转基因小鼠的皮肤肿瘤发生有促进作用，对NBR大鼠的皮肤肿瘤发生也有促进作用。无机砷（亚砷酸盐和砷酸盐）在大多数哺乳动物体内被代谢为一甲基胂酸（MMA）、DMA和氧化三甲基胂（TMAO）。本文研究了亚砷酸钠及其相关的有机砷（MMA、DMA、TMAO）对大鼠亚多器官致癌试验的促进作用。关于膀胱癌的发生，DMA最强烈地增强了肿瘤诱导，其次是MMA和TMAO，而AsBe和NaAsIII没有。膀胱癌发生的增强与砷的一种未知尿代谢产物的产生有关。这些结果表明，MMA和TMAO具有致癌潜力，以及DMA。

项目成果

Wei,M.,Wanibashi,H., et al.: "Urinary bladder carcinogenecity of dimethylarsinic acid in F344 rats."Carcinogenesis. 20. 1873-1876 (1999)

Wei，M.，Wanibashi，H.，等人：“二甲基胂酸对 F344 大鼠膀胱的致癌性。”致癌作用。

Li, W., Wanibuchi, H., et al.: "Promotion of NCI-Black-Reiter male rat bladder carcinogenesis by dimethylarsinic acid an organic arsenic compound"Cancer Lett.. 134. 29-36 (1998)

Li，W.，Wanibuchi，H.，等人：“有机砷化合物二甲基胂酸促进 NCI-Black-Reiter 雄性大鼠膀胱癌发生”Cancer Lett.. 134. 29-36 (1998)

Wei, M., Wanibuchi, H., et al.: "Urinary bladder carcinogenicity of dimethylarsinic acid in male F344 rats"Carcinogenesis. 20. 1873-1876 (1999)

Wei, M., Wanibuchi, H., 等人：“二甲基胂酸对雄性 F344 大鼠的膀胱致癌性”致癌作用。

Fukushima, S., Wanibuchi, H. et al.: "Urinary bladder cancer. In: Carcinogenicity. (eds.) Kitchin, K.T.,"Marcel Dekker, Inc.,. 895 (1999)

Fukushima, S., Wanibuchi, H. 等人：“膀胱癌。在：致癌性。（编辑）Kitchin, K.T.”Marcel Dekker, Inc.,。

Yoshida,K.: "The urinary excretion of arsenic metabolites after a single oral administration of dimethylarsinic acid to rats." Environ Contam.Toxicol.32. 416-421 (1997)

Yoshida,K.：“大鼠单次口服二甲基胂酸后砷代谢物的尿排泄。”