Reactive oxygen species in choline deficiency induced carcinogenesis and nitrone inhibition
Reactive oxygen species in choline deficiency induced carcinogenesis and nitrone inhibition
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DOI：
10.1023/a:1015910306026
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发表时间：
2002-05-01
影响因子：
4.3
通讯作者：
Konishi, Y
中科院分区：
文献类型：
--
作者：
Floyd, RA;Kotake, Y;Konishi, Y
活性氧和自由基过程多年来一直被认为在癌症发展中很重要。许多研究表明，胆碱缺乏诱导的肝癌模型显著涉及活性氧。我们提出了一个总结，在我们的原始研究中，这个模型在过去的4年中获得的结果。我们已经表明，α-苯基-叔丁基硝酮（PBN）和它的一些羟基化衍生物（4-和3-羟基化化合物）防止在这个模型中的肝癌发生。机制研究已经证明，从喂食胆碱缺乏限定氨基酸饮食的大鼠的肝脏分离的线粒体产生显著多得多的H2 O2/氧化的NADH还原当量。基于这些观察结果，我们假设H2 O2是该模型中的主要致癌因素。基于PBN对分离线粒体作用的研究，我们假设PBN的抑制作用涉及抑制线粒体的H2 O2产生并通常降低癌前病变内的氧化应激。硝酮化合物活性的净效应似乎是由于它们能够将细胞凋亡/肿瘤倾向平衡向肿瘤前病变内细胞的细胞凋亡转移。这被认为是肿瘤前病变的大小显著减小的主要原因，以及硝酮在该模型中是有效的抗癌剂的原因。
Reactive oxygen species and free radical processes have been considered important in cancer development for many years. Much research demonstrates that the choline-deficiency induced hepatocarcinogenesis model prominently involves reactive oxygen species. We present a summary of results obtained in our original studies of this model over the last 4 years. We have shown that alpha-phenyl-tert-butyl nitrone (PBN) and some of its hydroxylated derivatives (the 4- and 3-hydroxylated compounds) prevent hepatocarcinogenesis in this model. Mechanistic studies have demonstrated that isolated mitochondria from the livers of rats fed the choline-deficiency defined amino acid diet produce significantly much more H2O2 per NADH reducing equivalents oxidized. Based on these observations, we postulate that H2O2 is a primary carcinogenic factor in this model. Based on studies of the action of PBN on isolated mitochondria, we postulate that the inhibiting action of PBN involves suppression of H2O2 production of mitochondria and generally decreasing the oxidative stress within the preneoplastic lesions. The net effect of the activity of the nitrone compounds appears to be due to their ability to shift the apoptosis/neoplastic tendency balance toward apoptosis of the cells within the preneoplastic lesions. This is considered to be the primary reason the size of the preneoplastic lesions are significantly decreased and why the nitrones are potent anti-carcinogenic agents in this model.