Iqbal Mohammad, Sharma Som Datta, Okada Shigeru
Department of Pathological Research, Faculty of Medicine, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Redox Rep. 2004;9(3):167-72. doi: 10.1179/135100004225005174.
Probucol, a clinically used cholesterol lowering and antioxidant drug, was investigated for possible protection against lipid peroxidation and DNA damage induced by iron nitrilotriacetate (Fe-NTA) plus hydrogen peroxide (H2O2). Fe-NTA is a potent nephrotoxic agent and induces acute and subacute renal proximal tubular necrosis by catalyzing the decomposition of H2O2-derived production of hydroxyl radicals, which are known to cause lipid peroxidation and DNA damage. Fe-NTA is associated with a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation and DNA damage are the principal manifestation of Fe-NTA induced toxicity, which could be mitigated by probucol. Incubation of renal microsomal membrane and/or calf thymus DNA with H2O2 (40 mM) in the presence of Fe-NTA (0.1 mM) induces renal microsomal lipid peroxidation and DNA damage to about 2.4-fold and 5.9-fold, respectively, as compared to control (P < 0.05). Induction of renal microsomal lipid peroxidation and DNA damage was inhibited by probucol in a concentration-dependent manner. In lipid peroxidation protection studies, probucol treatment showed a concentration-dependent inhibition (10-34% inhibition; P < 0.05) of Fe-NTA plus H2O2-induced lipid peroxidation as measured by thiobarbituric acid reacting species' (TBARS) formation in renal microsomes. Similarly, in DNA damage protection studies, probucol treatment also showed a concentration-dependent strong inhibition (36-71% inhibition; P < 0.05) of DNA damage. From these studies, it was concluded that probucol inhibits peroxidation of microsomal membrane lipids and DNA damage induced by Fe-NTA plus H2O2. However, because the lipid peroxidation and DNA damage studied here are regarded as early markers of carcinogenesis, we suggest that probucol may be developed as a cancer chemopreventive agent against renal carcinogenesis and other adverse effects of Fe-NTA exposure in experimental animals, in addition to being a cholesterol-lowering drug, useful for the control of hypercholestrolemia.
普罗布考是一种临床使用的降胆固醇和抗氧化药物，本研究旨在探讨其对次氮基三乙酸铁（Fe-NTA）加过氧化氢（H2O2）诱导的脂质过氧化和DNA损伤是否具有保护作用。Fe-NTA是一种强效肾毒性剂，通过催化H2O2衍生的羟自由基生成，诱导急性和亚急性肾近端小管坏死，已知羟自由基会导致脂质过氧化和DNA损伤。Fe-NTA与啮齿动物肾腺癌的高发病率有关。脂质过氧化和DNA损伤是Fe-NTA诱导毒性的主要表现，而普罗布考可以减轻这种毒性。与对照组相比，在Fe-NTA（0.1 mM）存在的情况下，用H2O2（40 mM）孵育肾微粒体膜和/或小牛胸腺DNA可分别诱导肾微粒体脂质过氧化和DNA损伤至约2.4倍和5.9倍（P < 0.05）。普罗布考以浓度依赖的方式抑制肾微粒体脂质过氧化和DNA损伤的诱导。在脂质过氧化保护研究中，通过肾微粒体中硫代巴比妥酸反应物质（TBARS）的形成来衡量，普罗布考处理显示出对Fe-NTA加H2O2诱导的脂质过氧化的浓度依赖性抑制（抑制率为10-34%；P < 0.05）。同样，在DNA损伤保护研究中，普罗布考处理也显示出对DNA损伤的浓度依赖性强烈抑制（抑制率为36-71%；P < 0.05）。从这些研究得出结论，普罗布考可抑制Fe-NTA加H2O2诱导的微粒体膜脂质过氧化和DNA损伤。然而，由于这里研究的脂质过氧化和DNA损伤被视为致癌作用的早期标志物，我们建议除了作为一种降胆固醇药物用于控制高胆固醇血症外，普罗布考还可开发成为一种癌症化学预防剂，用于预防实验动物中的肾癌发生以及Fe-NTA暴露的其他不良影响。
