Rahman Ayesha, Ahmed Salahuddin, Vasenwala Shaista M, Athar Mohammad
Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, India.
Arch Biochem Biophys. 2003 Oct 1;418(1):71-9. doi: 10.1016/s0003-9861(03)00365-5.
Ferric nitrilotriacetate (Fe-NTA), a common water pollutant and a known renal carcinogen, acts through the generation of oxidative stress and hyperproliferative response. In the present study, we show that the nitric oxide (NO) generated by the administration of glyceryl trinitrate (GTN) affords protection against Fe-NTA-induced oxidative stress and proliferative response. Administration of Fe-NTA resulted in a significant (P<0.001) depletion of renal glutathione (GSH) content with concomitant increase in lipid peroxidation and elevated tissue damage marker release in serum. Parallel to these changes, Fe-NTA also caused down-regulation of GSH metabolizing enzymes including glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase and several fold induction in ornithine decarboxylase (ODC) activity and rate of DNA synthesis. Subsequent exogenous administration of GTN at doses of 3 and 6mg/kg body weight resulted in significant (P<0.001) recovery of GSH metabolizing enzymes and amelioration of tissue GSH content, in a dose-dependent manner. GTN administration also inhibited malondialdehyde (MDA) formation, induction of ODC activity, enhanced rate of DNA synthesis, and pathological deterioration in a dose-dependent fashion. Further, administration of NO inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), exacerbated Fe-NTA-induced oxidative tissue injury, hyperproliferative response, and pathological damage. Overall, the study suggests that NO administration subsequent to Fe-NTA affords protection against ROS-mediated damage induced by Fe-NTA.
次氮基三乙酸铁（Fe-NTA）是一种常见的水污染物，也是一种已知的肾致癌物，其作用机制是产生氧化应激和过度增殖反应。在本研究中，我们发现，施用硝酸甘油（GTN）所产生的一氧化氮（NO）可抵御Fe-NTA诱导的氧化应激和增殖反应。施用Fe-NTA导致肾脏谷胱甘肽（GSH）含量显著降低（P<0.001），同时脂质过氧化增加，血清中组织损伤标志物释放升高。与这些变化同时发生的是，Fe-NTA还导致GSH代谢酶下调，包括谷胱甘肽过氧化物酶（GPx）、谷胱甘肽还原酶（GR）和谷胱甘肽-S-转移酶，以及鸟氨酸脱羧酶（ODC）活性和DNA合成速率诱导增加数倍。随后以3和6mg/kg体重的剂量外源施用GTN，导致GSH代谢酶显著恢复（P<0.001），组织GSH含量改善，呈剂量依赖性。施用GTN还以剂量依赖性方式抑制丙二醛（MDA）形成、ODC活性诱导、DNA合成速率增加和病理恶化。此外，施用NO抑制剂N（G）-硝基-L-精氨酸甲酯（L-NAME）会加剧Fe-NTA诱导的氧化性组织损伤、过度增殖反应和病理损伤。总体而言，该研究表明，在Fe-NTA之后施用NO可抵御Fe-NTA诱导的ROS介导的损伤。
