Ganther H E
Department of Nutritional Sciences, University of Wisconsin, 1415 Linden Drive, Madison, WI 53706, USA.
Carcinogenesis. 1999 Sep;20(9):1657-66. doi: 10.1093/carcin/20.9.1657.
Numerous studies in animal models and more recent studies in humans have demonstrated cancer chemopreventive effects with Se. There is extensive evidence that monomethylated forms of Se are critical metabolites for chemopreventive effects of Se. Induction of apoptosis in transformed cells is an important chemopreventive mechanism. Apoptosis can be triggered by micromolar levels of monomethylated forms of Se independent of DNA damage and in cells having a null p53 phenotype. Cell cycle protein kinase cdk2 and protein kinase C are strongly inhibited by various forms of Se. Inhibitory mechanisms involving modification of cysteine residues in proteins by Se have been proposed that involve formation of Se adducts of the selenotrisulfide (S-Se-S) or selenenylsulfide (S-Se) type or catalysis of disulfide formation. Selenium may facilitate reactions of protein cysteine residues by the transient formation of more reactive S-Se intermediates. A novel chemopreventive mechanism is proposed involving Se catalysis of reversible cysteine/disulfide transformations that occur in a number of redox-regulated proteins, including transcription factors. A time-limited activation mechanism for such proteins, with deactivation facilitated by Se, would allow normalization of critical cellular processes in the early stages of transformation. There is uncertainty at the present time regarding the role of selenoproteins in chemoprevention model systems where supranutritional levels of Se are employed. Mammalian thioredoxin reductase is one selenoprotein that shows increased activity with Se supplementation in the nutritional to supranutritional range. Enhanced thioredoxin reduction could have beneficial effects in oxidative stress, but possible adverse effects are considered. Other functions of thioredoxin reductase may be relevant to cell signaling pathways. The functional status of the thioredoxin/thioredoxin reductase system during in vivo chemoprevention with Se has not been established. Some in vitro studies have shown inhibitory effects of Se on the thioredoxin system correlated with growth inhibition by Se. A potential inactivating mechanism for thioredoxin reductase or other selenoenzymes involving formation of a stable diselenide form resistant to reduction is discussed. New aspects of Se biochemistry and possible functions of new selenoproteins in chemoprevention are described.
在动物模型中的大量研究以及最近在人体中的研究均已证明硒具有癌症化学预防作用。有大量证据表明，单甲基化形式的硒是硒发挥化学预防作用的关键代谢产物。诱导转化细胞凋亡是一种重要的化学预防机制。微摩尔水平的单甲基化形式的硒可独立于DNA损伤并在p53表型缺失的细胞中触发凋亡。细胞周期蛋白激酶cdk2和蛋白激酶C受到各种形式硒的强烈抑制。有人提出了涉及硒对蛋白质中半胱氨酸残基进行修饰的抑制机制，其中包括形成硒代三硫化物（S-Se-S）或硒代亚硫化物（S-Se）类型的硒加合物或催化二硫键形成。硒可能通过瞬时形成反应性更强的S-Se中间体来促进蛋白质半胱氨酸残基的反应。有人提出了一种新的化学预防机制，涉及硒催化在包括转录因子在内的许多氧化还原调节蛋白中发生的可逆半胱氨酸/二硫键转化。此类蛋白的限时激活机制以及由硒促进的失活，将使转化早期阶段的关键细胞过程正常化。目前，在使用超营养水平硒的化学预防模型系统中，硒蛋白的作用尚不确定。哺乳动物硫氧还蛋白还原酶是一种硒蛋白，在营养至超营养范围内补充硒时其活性会增加。增强的硫氧还蛋白还原在氧化应激中可能具有有益作用，但也考虑到了可能的不利影响。硫氧还蛋白还原酶的其他功能可能与细胞信号通路相关。在体内用硒进行化学预防期间，硫氧还蛋白/硫氧还蛋白还原酶系统的功能状态尚未确定。一些体外研究表明，硒对硫氧还蛋白系统的抑制作用与硒对生长的抑制作用相关。讨论了硫氧还蛋白还原酶或其他硒酶的一种潜在失活机制，该机制涉及形成一种对还原具有抗性的稳定二硒化物形式。描述了硒生物化学的新方面以及新硒蛋白在化学预防中的可能功能。
