Biochemistry Graduate Programme and Department of Biological Sciences, Middle East Technical University, 06531 Ankara, Turkey.
J Pharm Pharm Sci. 2010;13(2):231-41.
Idarubicin is a synthetic anthracycline anticancer drug widely used in the treatment of some hematological malignancies. The studies in our laboratory have clearly demonstrated that idarubicin can undergo reductive bioactivation by NADPH-cytochrome P450 reductase to free radicals with resulting formation of DNA strand breaks, which can potentially contribute to its genotoxic effects [Celik, H., Arinç, E., Bioreduction of idarubicin and formation of ROS responsible for DNA cleavage by NADPH-cytochrome P450 reductase and its potential role in the antitumor effect. J Pharm Pharm Sci, 11(4):68-82, 2008]. In the current study, our aim was to investigate the possible protective effects of several phenolic antioxidants, quercetin, rutin, naringenin, resveratrol and trolox, against the DNA-damaging effect of idarubicin originating from its P450 reductase-catalyzed bioactivation.
DNA damage was measured by detecting single-strand breaks in plasmid pBR322 DNA using a cell-free agarose gel method.
Our results indicated that, among the compounds tested, quercetin was the most potent antioxidant in preventing DNA damage. Quercetin significantly decreased the extent of DNA strand breaks in a dose-dependent manner; 100 microM of quercetin almost completely inhibited the DNA strand breakage. Unlike quercetin, its glycosidated conjugate rutin, failed to provide any significant protection against idarubicin-induced DNA strand breaks except at the highest concentration tested (2 mM). The protective effects of other antioxidants were significantly less than that of quercetin even at high concentrations. Quercetin was found to be also an effective protector against DNA damage induced by mitomycin C.
We conclude that quercetin, one of the most abundant flavonoids in the human diet, is highly effective in reducing the DNA damage caused by the antitumor agents, idarubicin and mitomycin C, following bioactivation by P450 reductase.
柔红霉素是一种广泛用于治疗某些血液恶性肿瘤的合成蒽环类抗癌药物。我们实验室的研究清楚地表明，柔红霉素可以通过 NADPH-细胞色素 P450 还原酶进行还原性生物激活，产生自由基，从而导致 DNA 链断裂，这可能有助于其遗传毒性作用[Celik，H.，Arinç，E.，柔红霉素的生物还原和 NADPH-细胞色素 P450 还原酶负责 DNA 断裂的 ROS 形成及其在抗肿瘤作用中的潜在作用。J Pharm Pharm Sci，11（4）：68-82，2008]。在本研究中，我们的目的是研究几种酚类抗氧化剂（槲皮素、芦丁、柚皮苷、白藜芦醇和 Trolox）对柔红霉素通过 P450 还原酶催化的生物激活产生的 DNA 损伤的可能保护作用。
使用无细胞琼脂糖凝胶法检测质粒 pBR322 DNA 的单链断裂来测量 DNA 损伤。
我们的结果表明，在所测试的化合物中，槲皮素是预防 DNA 损伤的最有效抗氧化剂。槲皮素以剂量依赖性方式显著降低 DNA 链断裂的程度；100μM 的槲皮素几乎完全抑制 DNA 链断裂。与槲皮素不同，其糖苷化缀合物芦丁除在测试的最高浓度（2mM）外，不能提供任何对抗柔红霉素诱导的 DNA 链断裂的显著保护作用。即使在高浓度下，其他抗氧化剂的保护作用也明显小于槲皮素。发现槲皮素也是对抗 P450 还原酶生物激活后由丝裂霉素 C 引起的 DNA 损伤的有效保护剂。
我们得出结论，槲皮素是人类饮食中最丰富的类黄酮之一，在降低由 P450 还原酶生物激活的抗肿瘤药物柔红霉素和丝裂霉素 C 引起的 DNA 损伤方面非常有效。
