Giri U, Iqbal M, Athar M
Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
Int J Oncol. 1999 Apr;14(4):799-806. doi: 10.3892/ijo.14.4.799.
Earlier we have shown that ferric-nitrilotriacetate (Fe-NTA) is a hepatic as well as renal tumor promoter and acts by elaborating oxidative stress. In this study we show that copper-nitrilotriacetate (Cu-NTA) is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen. Similar to Fe-NTA, Cu-NTA has an ability to induce hepatic ornithine decarboxylase (ODC) activity dose-dependently. The maximum induction in hepatic ODC activity was observed 12 h after Cu-NTA treatment. However, renal ODC activity showed no significant changes at any time point and dose regimen studied. Similarly, hepatic and renal DNA synthesis which are measured as [3H]thymidine incorporation were increased dose-dependently in both the organs after Cu-NTA treatment. Unlike Fe-NTA, Cu-NTA administration had no significant effect on hepatic and renal glutathione, and on the activities of glutathione reductase, glutathione-S-transferase and catalase. In liver, saline-alone, DEN-alone, Cu-NTA-alone or DEN + Cu-NTA treated animals showed no hepatic tumors. Liver histology from only DEN-initiated and saline-treated control animals showed occasional appearance of a typical cell with large nucleus. Treatment of Cu-NTA to uninitiated and initiated animals showed more or less similar hepatic histology. Treatment of Cu-NTA to DEN-initiated animals resulted in the proliferative changes characterized by extensive hepatocellular hyperplasia. In case of kidney, the treatment of Cu-NTA to both the DEN-initiated and uninitiated animals led to the development of renal cell tumors. Treatment of Cu-NTA to the uninitiated animals produced renal cell tumors in about 18.7% animals. However, treatment of Cu-NTA to the DEN-initiated animals led to the development of renal cell tumors in 77.7% animals, of which most of the tumors were bilateral. However, DEN-initiated and saline-treated control animals showed no evidence of tumors. Our data indicate that Cu-NTA is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen.
我们之前已经表明，次氮基三乙酸铁（Fe-NTA）是一种肝脏和肾脏肿瘤促进剂，其作用机制是产生氧化应激。在本研究中，我们表明次氮基三乙酸铜（Cu-NTA）在肝脏和肾脏中都是增殖反应的有效诱导剂，但它是一种完全性肾致癌物。与Fe-NTA类似，Cu-NTA能够剂量依赖性地诱导肝脏鸟氨酸脱羧酶（ODC）活性。在Cu-NTA处理后12小时观察到肝脏ODC活性的最大诱导。然而，在所研究的任何时间点和剂量方案下，肾脏ODC活性均未显示出显著变化。同样，以[3H]胸苷掺入量衡量的肝脏和肾脏DNA合成在Cu-NTA处理后在两个器官中均呈剂量依赖性增加。与Fe-NTA不同，Cu-NTA给药对肝脏和肾脏谷胱甘肽以及谷胱甘肽还原酶、谷胱甘肽-S-转移酶和过氧化氢酶的活性没有显著影响。在肝脏中，单独给予生理盐水、单独给予二乙基亚硝胺（DEN）、单独给予Cu-NTA或给予DEN + Cu-NTA的动物均未出现肝脏肿瘤。仅由DEN启动并经生理盐水处理的对照动物的肝脏组织学偶尔可见一个典型的大核细胞。对未启动和已启动动物给予Cu-NTA的处理显示出或多或少相似的肝脏组织学。对DEN启动的动物给予Cu-NTA处理导致以广泛的肝细胞增生为特征的增殖性变化。在肾脏方面，对DEN启动和未启动的动物给予Cu-NTA处理均导致肾细胞肿瘤的发生。对未启动动物给予Cu-NTA处理在约18.7%的动物中产生了肾细胞肿瘤。然而，对DEN启动的动物给予Cu-NTA处理导致77.7%的动物发生肾细胞肿瘤，其中大多数肿瘤是双侧的。然而 D EN启动并经生理盐水处理的对照动物未显示出肿瘤迹象。我们的数据表明，Cu-NTA在肝脏和肾脏中都是增殖反应的有效诱导剂，但它是一种完全性肾致癌物。
