Athar M, Iqbal M
Department of Medical Elementology and Toxicology, Hamdard University (Jamia Hamdard), New Delhi, India.
Carcinogenesis. 1998 Jun;19(6):1133-9. doi: 10.1093/carcin/19.6.1133.
Ferric nitrilotriacetate (Fe-NTA) is a known complete renal carcinogen. In this study we show that Fe-NTA is a potent inducer of renal ornithine decarboxylase (ODC) activity and DNA synthesis and promoter of N-diethylnitrosamine (DEN)-induced renal tumorigenesis in rat. Fe-NTA induced renal ODC activity several fold as compared with saline-treated rats. Renal DNA synthesis, measured as [3H]thymidine incorporation into DNA, was increased after Fe-NTA treatment. Similar to other known tumor promoters, Fe-NTA also depleted the antioxidant armory of the tissue. It depleted glutathione (GSH) levels to approximately 55% of saline-treated controls. It also led to a dose-dependent decrease in the activities of glutathione reductase and glutathione S-transferase. Similarly, activities of catalase, glutathione peroxidase and glucose 6-phosphate dehydrogenase decreased significantly (45-65%). In contrast, gamma-glutamyl transpeptidase activity showed an increase. The maximum changes in activities of these enzymes could be observed at 12 h following Fe-NTA treatment. In addition, Fe-NTA augmented renal microsomal lipid peroxidation >150% over saline-treated controls, which was concomitant with the alterations in GSH metabolizing enzymes and depletion of the antioxidant armory. These effects were alleviated in rats which received a pretreatment with an antioxidant, BHA or BHT. Fe-NTA promoted DEN-induced renal tumorigenesis. In saline alone- and DEN alone-treated animals no tumors could be recorded, whereas in Fe-NTA alone-treated animals 17% tumor incidence was observed. However, in DEN-initiated and Fe-NTA-promoted animals tumor incidence increased to 71%. Our results show that Fe-NTA induces oxidative stress in the kidney and decreases antioxidant defenses, as indicated by the fall in GSH level and in the activities of glutathione peroxidase and catalase. Concomitantly, Fe-NTA increases ODC activity and DNA synthesis, which may be compensatory changes following oxidative injury to renal cells in addition to providing a strong stimulus for renal tumor promotion. Thus oxidative stress and impaired antioxidant defenses induced by Fe-NTA in the kidney may contribute to the observed nephrotoxicity and carcinogenicity.
次氮基三乙酸铁（Fe-NTA）是一种已知的完全性肾致癌物。在本研究中，我们表明Fe-NTA是肾鸟氨酸脱羧酶（ODC）活性和DNA合成的强效诱导剂，也是N-二乙基亚硝胺（DEN）诱导大鼠肾肿瘤发生的促进剂。与盐水处理的大鼠相比，Fe-NTA诱导的肾ODC活性增加了几倍。以[³H]胸腺嘧啶掺入DNA来衡量，Fe-NTA处理后肾DNA合成增加。与其他已知的肿瘤促进剂类似，Fe-NTA也耗尽了组织的抗氧化防御能力。它将谷胱甘肽（GSH）水平降低至盐水处理对照组的约55%。它还导致谷胱甘肽还原酶和谷胱甘肽S-转移酶的活性呈剂量依赖性下降。同样，过氧化氢酶、谷胱甘肽过氧化物酶和葡萄糖6-磷酸脱氢酶的活性显著下降（45%-65%）。相反，γ-谷氨酰转肽酶活性增加。这些酶活性的最大变化可在Fe-NTA处理后12小时观察到。此外，与盐水处理的对照组相比，Fe-NTA使肾微粒体脂质过氧化增加超过150%，这与GSH代谢酶的改变和抗氧化防御能力的耗尽相伴。在接受抗氧化剂丁基羟基茴香醚（BHA）或丁基化羟基甲苯（BHT）预处理的大鼠中，这些效应得到缓解。Fe-NTA促进DEN诱导的肾肿瘤发生。在仅用盐水处理和仅用DEN处理的动物中未记录到肿瘤，而在仅用Fe-NTA处理的动物中观察到17%的肿瘤发生率。然而，在DEN启动且Fe-NTA促进的动物中，肿瘤发生率增加到71%。我们的结果表明，Fe-NTA在肾脏中诱导氧化应激并降低抗氧化防御能力，如GSH水平以及谷胱甘肽过氧化物酶和过氧化氢酶活性下降所示。同时，Fe-NTA增加ODC活性和DNA合成，这除了为肾肿瘤促进提供强烈刺激外，可能是肾细胞氧化损伤后的代偿性变化。因此，Fe-NTA在肾脏中诱导的氧化应激和受损的抗氧化防御可能导致所观察到的肾毒性和致癌性。
