Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical.
Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical.
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发表时间：
1986-03
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通讯作者：
J. Doroshow;K. Davies
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作者：
J. Doroshow;K. Davies
在随附的论文中（Davies，K. J.A.，和Doroshow，J.A.（1986）J.Biol.Chem.261，3060-3067），我们已经证明蒽环类抗生素在线粒体电子传递链的复合物I处被还原成半醌形式。在本研究中提出的实验中，我们研究了阿霉素（阿霉素），柔红霉素，和相关的quinandrius抗癌剂对超氧化物，过氧化氢和羟基自由基的生产牛心亚线粒体颗粒的制剂的影响。从（平均值+/- S.E.）1.6+/- 0.2至69.6 +/- 2.7或32.1 +/- 1.5 nmol X min-1 X mg-1。然而，蒽环类5-亚氨基柔红霉素，其中亚胺基团已被取代的C环醌部分，并没有增加超氧化物的生产超过对照水平。在鱼藤酮的存在下，在可比的实验条件下，氧消耗和超氧化物形成的初始速率是相同的。此外，用阿霉素（200 μ M）处理亚线粒体颗粒后，H2 O2的产生从不可检测的对照水平增加到2.2 +/- 0.3 nmol X min-1 X mg-1。羟基自由基，或相关的化学氧化剂，也检测到后，蒽环类抗生素添加到该系统中的ESR光谱使用的自旋陷阱5，5-二甲基吡咯啉-N-氧化物和气相色谱定量的甲烷产生的二甲基亚砜。羟基自由基的产生，这是铁依赖在这个系统中，发生在一个非线性的方式与一个初始的滞后阶段，由于需要过氧化氢积累。我们还发现，两个quinandrexate抗癌剂，产生较少的心脏毒性比蒽环类药物，丝裂霉素C，和米托蒽醌，刺激显着减少或没有羟基自由基产生的亚线粒体颗粒。这些实验表明，蒽环类抗生素对心肌线粒体的损伤可能是由于NADH脱氢酶在蒽环类抗生素代谢过程中产生羟基自由基所致。
In the accompanying paper (Davies, K. J. A., and Doroshow, J. A. (1986) J. Biol. Chem. 261, 3060-3067), we have demonstrated that anthracycline antibiotics are reduced to the semiquinone form at Complex I of the mitochondrial electron transport chain. In the experiments presented in this study we examined the effects of doxorubicin (Adriamycin), daunorubicin, and related quinonoid anticancer agents on superoxide, hydrogen peroxide, and hydroxyl radical production by preparations of beef heart submitochondrial particles. Superoxide anion formation was stimulated from (mean +/- S.E.) 1.6 +/- 0.2 to 69.6 +/- 2.7 or 32.1 +/- 1.5 nmol X min-1 X mg-1 by the addition of 90 microM doxorubicin or daunorubicin, respectively. However, the anthracycline 5-iminodaunorubicin, in which an imine group has been substituted in the C ring quinone moiety, did not increase superoxide production over control levels. In the presence of rotenone, initial rates of oxygen consumption and superoxide formation were identical under comparable experimental conditions. Furthermore, H2O2 production increased from undetectable control levels to 2.2 +/- 0.3 nmol X min-1 X mg-1 after treatment of submitochondrial particles with doxorubicin (200 microM). The hydroxyl radical, or a related chemical oxidant, was also detected after the addition of an anthracycline to this system by both ESR spectroscopy using the spin trap 5,5-dimethylpyrroline-N-oxide and by gas chromatographic quantitation of CH4 produced from dimethyl sulfoxide. Hydroxyl radical production, which was iron-dependent in this system, occurred in a nonlinear fashion with an initial lag phase due to a requirement for H2O2 accumulation. We also found that two quinonoid anti-cancer agents which produce less cardiotoxicity than the anthracyclines, mitomycin C, and mitoxantrone, stimulated significantly less or no hydroxyl radical production by submitochondrial particles. These experiments suggest that injury to cardiac mitochondria which is produced by anthracycline antibiotics may result from the generation of the hydroxyl radical during anthracycline metabolism by NADH dehydrogenase.