Cancer chemoprevention: Selenium as a prooxidant not an antioxidant
Cancer chemoprevention: Selenium as a prooxidant not an antioxidant
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DOI：
10.1016/j.mehy.2006.01.058
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发表时间：
2006-01-01
影响因子：
4.7
通讯作者：
Drake, E. N.
中科院分区：
文献类型：
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作者：
Drake, E. N.
尽管在美国，每日膳食硒的平均摄入量一直高于成人推荐摄入量（55 μ g硒/天），但每日200 μ g硒的超营养补充剂已被证明对几种癌症，特别是前列腺癌具有化学预防作用。本文的假设认为，具有最大抗癌效力的硒化合物可能是硒处于+4氧化态的亚硒酸钠和亚硒酸甲酯。这些化合物通过直接氧化含有关键硫醇的细胞底物来发挥其癌症化学预防作用，比缺乏氧化能力的硒代蛋氨酸和硒甲基硒半胱氨酸等更常用的补充剂更有效。硒酸盐（+6硒），亚硒酸盐（+4硒）的直接前体，可以被代谢还原，虽然不如以上提到的+4硒化合物有效，但似乎是比有机形式的膳食硒更有效的抗癌物质。细胞凋亡是一种重要的硒诱导的抗癌机制，它是通过细胞酶（如蛋白激酶C）催化区域内半胱氨酸簇中邻近巯基的直接氧化，以及与O-2反应产生超氧化物和其他活性氧（ROS）的CH3Se-的产生来完成的。激活的癌基因为硒诱导的前氧化细胞凋亡“预备”细胞，从而为“杀死”癌细胞提供必要的余地，同时使正常、健康的细胞不受伤害。硒醚，如硒代蛋氨酸和硒甲基硒半胱氨酸不是氧化剂，首先必须转化为甲基硒醇（CH3Se-），后者可以直接氧化成甲基硒酸。将蛋氨酸酶添加到七亚甲蛋氨酸中，或将β -酪氨酸添加到硒甲基硒半胱氨酸中，可迅速产生大量的甲基硒醇，甲基硒醇可能被氧化成甲基硒酸，或与O-2反应产生超氧化物和活性氧，从而产生与亚硒酸盐或甲基亚硒酸相当的抗癌活性。与亚硒酸盐或甲基亚硒酸相比，在癌细胞中产生凋亡所需的硒代蛋氨酸或硒甲基亚硒半胱氨酸相对较多，这可能是两种组织所需酶水平不同的结果。尽管许多研究一致表明，在与FDA目前允许的剂量相对应的剂量下，七硫代蛋氨酸是一种无效的抗癌剂，但在一项由nci资助的32,500人（III期）的SELECT试验中，它被选为硒干预剂，该试验测试硒和生育酚膳食补充剂单独或联合预防前列腺癌的有效性。2013年的数据显示，使用硒补充剂进行癌症化学预防的价值可能被低估了。(c) 2006 Elsevier Ltd.版权所有。
Although the average daily dietary selenium (Se) intake in the United States is consistently above the adult RDA of 55 mu g Se/day, supranutritional supplements of 200 mu g Se/day have been shown to provide chemopreventive benefits against several cancers, particularly prostate cancer. The hypothesis herein contends that selenium compounds with the greatest anticarcinogenic potency are likely to be sodium selenite with Se in the +4 oxidation state and methylseleninic acid. These compounds exert their cancer chemopreventive effects by directly oxidizing critical thiol-containing cellular substrates, and are more effective than the more frequently preferred (used) supplements of selenomethionine and Se-methylselenocysteine that lack oxidation capability. Selenate (+6 Se) the immediate precursor of selenite (+4 Se) can be metabolically reduced, and although less potent than the +4 Se compounds cited above, appears to be a more effective anticarcinogen than organic forms of dietary selenium.Apoptosis, an important, Se-induced anticarcinogenic mechanism, is accomplished by the direct oxidation of vicinal sulfhydryl groups in cysteine clusters within the catalytic domains of cellular enzymes (e.g., protein kinase C), and by the production of CH3Se-, which reacts with O-2 to generate superoxide and other reactive oxygen species (ROS). Activated oncogenes "prime" cells for Se-induced prooxidative apoptosis thereby providing the needed margin for "killing" cancer cells while leaving normal, healthy cells unharmed.Selenoethers, such as selenomethionine and Se-methylselenocysteine are not oxidizing agents, and first, must be converted to methylselenol (CH3Se-) that can be directly oxidized to methylseleninic acid. The addition of methioninase, to setenomethionine, or beta-tyase to Se-methylselenocysteine, rapidly produces significant amounts of methylselenol, which may be oxidized to methytseleninic acid or may react with O-2 to produce superoxide and ROS, resulting in anticarcinogenic activities comparable to selenite or methylseleninic acid. The relatively large amounts of selenomethionine or Se-methylselenocysteine needed to produce apoptosis in cancer cells compared with selenite or methylseleninic acid are a probable consequence of tow tissue levels of the required enzymes.Even though many studies have consistently shown that setenomethionine is an ineffective anticarcinogen at doses corresponding to those currently allowed by the FDA, it has been chosen as the Se intervention agent in the 32,500-man (phase III), NCI-funded SELECT trial, which tests the effectiveness of dietary supplements of dietary supplements of Se and tocopherol, individually or in combination, in the prevention of prostate cancer. In 2013, when the data are in, the value of using Se supplements for cancer chemoprevention is likely to be underestimated. (c) 2006 Elsevier Ltd. All rights reserved.