Umemura T, Hasegawa R, Sai-Kato K, Nishikawa A, Furukawa F, Toyokuni S, Uchida K, Inoue T, Kurokawa Y
Division of Toxicology, National Institute of Health Sciences, Setagaya-ku, Tokyo.
Jpn J Cancer Res. 1996 Sep;87(9):882-6. doi: 10.1111/j.1349-7006.1996.tb02115.x.
Ferric nitrilotriacetate (Fe-NTA) is a renal toxicant and carcinogen in rats and mice. We found that its administration results in formation of 4-hydroxy-2-nonenal (HNE) in the renal proximal tubule cells of rats, and 8-hydroxydeoxyguanosine (8-OHdG) adducts in their DNA, suggesting a role for oxidative stress. Since 2-mercaptoethane sulfonate (MESNA) and N-acetylcysteine (NAC), administered orally, have been shown to increase the kidney levels of free thiol groups, their influence on the renal toxicity and carcinogenicity induced by Fe-NTA was examined in the present study. Male Wistar rats were intraperitoneally injected with Fe-NTA (12 mg Fe/kg), and MESNA (100 mg/kg) or NAC (200 mg/kg) was given orally 1 h before and 1 h after this treatment. The animals were killed for tissue analyses 3 h after the Fe-NTA exposure. In accord with our previous reports, HNE-modified protein was detected in the proximal tubules of Fe-NTA-treated rats by means of immunohistochemistry. Likewise, levels of 8-OHdG in the renal nuclear DNA, lipid peroxides as thiobarbituric acid-reactive substances in the kidneys, and blood urea nitrogen and creatinine in the serum were significantly increased by the Fe-NTA treatment. All of these changes were completely inhibited by oral administration of MESNA or NAC. These results suggest that both of these compounds can prevent the oxidative stress induced by Fe-NTA.
次氮基三乙酸铁（Fe-NTA）对大鼠和小鼠具有肾脏毒性并可致癌。我们发现，给大鼠施用Fe-NTA会导致其肾近端小管细胞中形成4-羟基-2-壬烯醛（HNE），并在其DNA中形成8-羟基脱氧鸟苷（8-OHdG）加合物，这表明氧化应激发挥了作用。由于口服2-巯基乙烷磺酸盐（MESNA）和N-乙酰半胱氨酸（NAC）已被证明可提高肾脏中游离巯基的水平，因此在本研究中检测了它们对Fe-NTA诱导的肾脏毒性和致癌性的影响。雄性Wistar大鼠腹腔注射Fe-NTA（12 mg Fe/kg），并在该处理前1小时和处理后1小时口服MESNA（100 mg/kg）或NAC（200 mg/kg）。在Fe-NTA暴露3小时后处死动物进行组织分析。与我们之前的报告一致，通过免疫组织化学在Fe-NTA处理的大鼠近端小管中检测到HNE修饰的蛋白质。同样，Fe-NTA处理显著增加了肾脏核DNA中的8-OHdG水平、肾脏中作为硫代巴比妥酸反应性物质的脂质过氧化物水平以及血清中的血尿素氮和肌酐水平。口服MESNA或NAC可完全抑制所有这些变化。这些结果表明，这两种化合物均可预防Fe-NTA诱导的氧化应激。
