Iqbal Mohammad, Okazaki Yasumasa, Okada Shigeru
Biotechnology Research Institute, University Malaysia Sabah, Locked Bag No. 2073, 88999, Kotakinabalu, Sabah, Malaysia.
Mol Cell Biochem. 2007 Oct;304(1-2):61-9. doi: 10.1007/s11010-007-9486-6. Epub 2007 May 9.
Probucol is a clinically used cholesterol-lowering drug, with pronounced antioxidant properties. We have reported previously, that dietary supplementation of probucol enhances NAD(P)H:quinone reductase (Iqbal M, Okada S (2003) Pharmacol Toxicol 93:259-263) and inhibits Fe-NTA induced lipid peroxidation and DNA damage in vitro (Iqbal M, Sharma SD, Oakada (2004) Redox Rep 9:167-172). Further to this, in the present study, we evaluated the modulatory effect of probucol on iron nitrilotriacetae (Fe-NTA) dependent renal carcinogenesis, hyperproliferative response and oxidative stress. In Fe-NTA alone treated group, a 20% renal cell tumor incidence was recorded whereas, in N-diethylnitrosamine (DEN)-initiated and Fe-NTA promoted animals, the percentage tumor incidence was increased to 70% as compared with untreated controls. No tumor incidence was recorded in DEN-initiated, nonpromoted group. Diet supplemented with 1.0% probucol fed prior to, during and after Fe-NTA treatment in DEN-initiated animals afforded >65% protection in renal cell tumor incidence. Probucol fed diet pretreatment also resulted a significant and dose dependent inhibition of Fe-NTA induced renal ornithine decarboxylase (ODC) activity. In oxidative stress studies, Fe-NTA alone treatment enhanced lipid peroxidation, accompanied by a decrease in the level of GSH, activities of antioxidants and phase II metabolizing enzymes in kidney concomitant with histolopathological changes. These changes were significantly and dose-dependently alleviated by probucol fed diet. From this data, it can be concluded that probucol can modulates toxic and tumor promoting effects of Fe-NTA and can serve as a potent chemopreventive agent to suppress oxidant induced tissue injury and carcinogenesis, in addition to being a cholesterol lowering and anti-atherogenic drug.
普罗布考是一种临床使用的降胆固醇药物，具有显著的抗氧化特性。我们之前曾报道，饮食中补充普罗布考可增强NAD(P)H：醌还原酶（伊克巴尔M，冈田S（2003年）《药理学与毒理学》93：259 - 263），并在体外抑制Fe-NTA诱导的脂质过氧化和DNA损伤（伊克巴尔M，夏尔马SD，冈田（2004年）《氧化还原报告》9：167 - 172）。除此之外，在本研究中，我们评估了普罗布考对次氮基三乙酸铁（Fe-NTA）依赖性肾致癌作用、过度增殖反应和氧化应激的调节作用。在仅用Fe-NTA处理的组中，记录到肾细胞肿瘤发生率为20%，而在经N-二乙基亚硝胺（DEN）启动且Fe-NTA促进的动物中，与未处理的对照组相比，肿瘤发生率百分比增加到了70%。在DEN启动、未促进的组中未记录到肿瘤发生率。在DEN启动的动物中，在Fe-NTA处理之前、期间和之后喂食添加1.0%普罗布考的饮食，在肾细胞肿瘤发生率方面提供了>65%的保护。普罗布考饮食预处理还导致Fe-NTA诱导的肾鸟氨酸脱羧酶（ODC）活性受到显著且剂量依赖性的抑制。在氧化应激研究中，仅用Fe-NTA处理会增强脂质过氧化，同时伴随着肾脏中谷胱甘肽水平降低、抗氧化剂和II相代谢酶活性降低以及组织病理学变化。这些变化通过喂食普罗布考的饮食得到了显著且剂量依赖性的缓解。从这些数据可以得出结论，普罗布考可以调节Fe-NTA的毒性和促肿瘤作用，并且除了作为一种降胆固醇和抗动脉粥样硬化药物外，还可以作为一种有效的化学预防剂来抑制氧化剂诱导的组织损伤和致癌作用。
