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首页> 外文期刊>Life sciences >Metabolic activation of mitomycin C by NADPH-ferredoxin reductase in vitro.
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Metabolic activation of mitomycin C by NADPH-ferredoxin reductase in vitro.

机译：NADPH-铁氧还蛋白还原酶在体外代谢丝裂霉素C。

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摘要

Mammalian NADPH-ferredoxin reductase (EC 1.18.1.2) functions in the mitochondrial electron transport chain for cytochrome P-450-dependent steroid hydroxylation. Significant homology of three-dimensional structure exists in the surroundings of FAD between NADPH-ferredoxin reductase and NADH-cytochrome b5 reductase. The latter is involved in the bioreduction of mitomycin C (MC), a prototype antitumor agent. In this study, we assessed the capacity of NADPH-ferredoxin reductase to activate MC. Mitomycin C increased the NADPH oxidase activity of NADPH-ferredoxin reductase. In the absence of ferredoxin, the Km value of NADPH-ferredoxin reductase for MC was 73.5 +/- 2.3 microM. While in the presence of 500 nM ferredoxin, a Lineweaver-Burk plot exhibited a biphasic curve. NADPH-ferredoxin reductase-mediated reduction of MC resulted in the formation of an alkylated complex of 4-(p-nitrobenzyl) pyridine and an increase in plasmide DNA single-strand breaks under hypoxic conditions. With the addition of 500 nM ferredoxin, the amount of the alkylated complex of 4-(p-nitrobenzyl) pyridine and the plasmide DNA single-strand breaks increased by 40% and 37%, respectively. However, neither alkylated complex of 4-(p-nitrobenzyl) pyridine nor DNA strand breaks was observed in the presence of SOD and catalase under aerobic conditions. These findings demonstrate that NADPH-ferredoxin reductase is capable of catalyzing the bioactivation of mitomycin C under hypoxic conditions in vitro.
机译：哺乳动物NADPH-铁氧还蛋白还原酶（EC 1.18.1.2）在线粒体电子传输链中发挥作用，以依赖于细胞色素P-450的类固醇羟基化。 NADPH-铁氧还蛋白还原酶和NADH-细胞色素b5还原酶之间的FAD存在三维结构的显着同源性。后者参与了抗肿瘤药物原型丝裂霉素C（MC）的生物还原。在这项研究中，我们评估了NADPH-铁氧还蛋白还原酶激活MC的能力。丝裂霉素C增加了NADPH-铁氧还蛋白还原酶的NADPH氧化酶活性。在没有铁氧还蛋白的情况下，MC的NADPH-铁氧还蛋白还原酶的Km值为73.5 +/- 2.3 microM。在存在500 nM铁氧还蛋白的情况下，Lineweaver-Burk图显示了双相曲线。 NADPH-铁氧还蛋白还原酶介导的MC还原导致在低氧条件下形成4-（对硝基苄基）吡啶的烷基化复合物并增加质粒DNA单链断裂。加入500 nM铁氧还蛋白后，4-（对硝基苄基）吡啶的烷基化复合物和质粒DNA单链断裂的数量分别增加了40％和37％。然而，在有氧条件下，在SOD和过氧化氢酶存在下，未观察到4-（对硝基苄基）吡啶的烷基化复合物或DNA链断裂。这些发现表明，NADPH-铁氧还蛋白还原酶能够在缺氧条件下体外催化丝裂霉素C的生物活化。

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