Peroxidase- and nitrite-dependent metabolism of the anthracycline anticancer agents daunorubicin and doxorubicin.
Peroxidase- and nitrite-dependent metabolism of the anthracycline anticancer agents daunorubicin and doxorubicin.
复制标题
蒽环类抗癌药物柔红霉素和阿霉素的过氧化物酶和亚硝酸盐依赖性代谢。
DOI：
10.1021/bi011869c
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发表时间：
2001
期刊：
影响因子：
2.9
通讯作者：
Britigan,BE
中科院分区：
文献类型：
--
作者：
Reszka,KJ;McCormick,ML;Britigan,BE
用分光光度法和EPR技术研究了在亚硝酸根存在和不存在的条件下，乳过氧化物酶（LPO）/H_2O_2和辣根过氧化物酶（HRP）/H_2O_2体系对抗癌药物蒽环类药物阿霉素（DXR）和柔红霉素（DNR）的氧化反应。我们报告LPO/H2 O2/NO2-导致蒽环类药物的吸收带快速和不可逆的损失，这表明其发色团的氧化降解。氧化的初始速率和程度都取决于NO2-浓度和pH值。当pH值从7变化到5时，初始速率降低，反应几乎在pH 5时停止。模型对苯二酚化合物2，5-二叔丁基对苯二酚被LPO/H2 O2氧化也依赖于NO2-;然而，与DNR和DXR相反，这种氧化在pH 5时最有效，表明LPO/H2 O2/NO2-能够有效地氧化简单的对苯二酚，即使是中性形式。在pH 5或pH 7下，HRP/H2 O2/NO2-氧化蒽环类抗生素的效率明显低于LPO/H2 O2/NO2-，这很可能是由于HRP/H2 O2代谢NO2-的速率较低。EPR研究表明，蒽环类和2，5-二叔丁基对苯二酚与LPO/H_2O_2/NO_2 ~-的相互作用可能通过对苯二酚部分的单电子氧化产生相应的半醌自由基。讨论了·NO2自由基（NO2-的推定LPO代谢物）在这些化合物氧化中的可能作用。由于在体内蒽环类药物可能与组织中的过氧化物酶、H2 O2和NO2-共定位，因此它们可能通过所提出的机制氧化。这些观察结果揭示了一种新的，过氧化物酶和亚硝酸盐依赖的机制，抗癌蒽环类药物的氧化转化，这可能是有关他们在体内的生物活性。
Oxidation of the anticancer anthracyclines doxorubicin (DXR) and daunorubicin (DNR) by lactoperoxidase(LPO)/H2O2and horseradish peroxidase(HRP)/H2O2systems in the presence and absence of nitrite (NO2-) has been investigated using spectrophotometric and EPR techniques. We report that LPO/H2O2/NO2-causes rapid and irreversible loss of anthracyclines' absorption bands, suggesting oxidative degradation of their chromophores. Both the initial rate and the extent of oxidation are dependent on both NO2-concentration and pH. The initial rate decreases when the pH is changed from 7 to 5, and the reaction virtually stops at pH 5. Oxidation of a model hydroquinone compound, 2,5-di-tert-butylhydroquinone, by LPO/H2O2is also dependent on NO2-; however, in contrast to DNR and DXR, this oxidation is most efficient at pH 5, indicating that LPO/H2O2/NO2-is capable of efficiently oxidizing simple hydroquinones even in the neutral form. Oxidation of anthracyclines by HRP/H2O2/NO2-is substantially less efficient relative to that by LPO/H2O2/NO2-at either pH 5 or pH 7, most likely due to the lower rate of NO2-metabolism by HRP/H2O2. EPR measurements show that interaction of anthracyclines and 2,5-di-tert-butylhydroquinone with LPO/H2O2/NO2-generates the corresponding semiquinone radicals presumably via one-electron oxidation of their hydroquinone moieties. The possible role of the•NO2radical, a putative LPO metabolite of NO2-, in oxidation of these compounds is discussed. Because in vivo the anthracyclines may co-localize with peroxidases, H2O2, and NO2-in tissues, their oxidation via the proposed mechanism is likely. These observations reveal a novel, peroxidase- and nitrite-dependent mechanism for the oxidative transformation of the anticancer anthracyclines, which may be pertinent to their biological activities in vivo.