In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention.
In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention.
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发表时间：
2000-06
期刊：
影响因子：
11.2
通讯作者：
Clement Ip;Henry J. Thompson;Zongjian Zhu;H. Ganther
中科院分区：
文献类型：
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作者：
Clement Ip;Henry J. Thompson;Zongjian Zhu;H. Ganther
先前的研究表明，β-裂解酶介导的硒-甲基硒代半胱氨酸的单甲基化硒代谢产物的生产是癌症化学预防的关键步骤。为了确认这一概念，本研究旨在评估甲基硒酸的活性，甲基硒酸是一种代表没有氨基酸部分的Se-甲基硒代半胱氨酸的简化版本的化合物，从而避免了对β-裂解酶作用的需要。在体外实验表明，甲基亚硒酸是更有效的抑制细胞积累和诱导细胞凋亡的TM 12（野生型p53）和TM 2 H（非功能性p53）小鼠乳腺增生性上皮细胞比硒-甲基硒代半胱氨酸，这些影响是不归因于DNA损伤，由彗星试验确定。在一般情况下，甲基硒酸产生了更强大的响应十分之一的硒-甲基硒代半胱氨酸的浓度。这些细胞系可能仅具有通过β-裂解酶从Se-甲基硒代半胱氨酸产生单甲基化硒物质的适度能力。相比之下，甲基亚硒酸已经作为一个预先形成的活性单甲基化代谢物，这可能是一个潜在的原因，为什么甲基亚硒酸的行动更迅速，发挥更强大的作用比硒-甲基硒代半胱氨酸在体外。有趣的是，这两种化合物之间的区别在体内消失，其中发现它们的癌症化学预防功效彼此非常相似[在甲基亚硝基脲和二甲基苯并（a）蒽大鼠乳腺肿瘤模型中]。β-裂合酶存在于许多组织中;因此，动物有足够的能力全身代谢硒-甲基硒代半胱氨酸。因此，如果β-裂合酶不再是限制因素，则Se-甲基硒代半胱氨酸将预期表现得像甲基亚硒酸。两者合计，目前在体外和体内的结果提供了强有力的证据，支持我们早期的假设，即一甲基硒代谢物是重要的癌症化学预防。甲基亚硒酸可能是一个很好的工具，特别是在细胞培养的分子机制研究，其中一些属性进行了讨论。
Previous research suggested that the beta-lyase-mediated production of a monomethylated selenium metabolite from Se-methylselenocysteine is a key step in cancer chemoprevention by this agent. In an attempt to affirm the concept, the present study was designed to evaluate the activity of methylseleninic acid, a compound that represents a simplified version of Se-methylselenocysteine without the amino acid moiety, thereby obviating the need for beta-lyase action. The in vitro experiments showed that methylseleninic acid was more potent than Se-methylselenocysteine in inhibiting cell accumulation and inducing apoptosis in TM12 (wild-type p53) and TM2H (nonfunctional p53) mouse mammary hyperplastic epithelial cells, and these effects were not attributable to DNA damage, as determined by the comet assay. In general, methylseleninic acid produced a more robust response at one-tenth the concentration of Se-methylselenocysteine. It is possible that these cell lines may have only a modest ability to generate a monomethylated selenium species from Se-methylselenocysteine via the beta-lyase enzyme. In contrast, methylseleninic acid already serves as a preformed active monomethylated metabolite, and this could be an underlying reason why methylseleninic acid acts more rapidly and exerts a more powerful effect than Se-methylselenocysteine in vitro. Interestingly, the distinction between these two compounds disappeared in vivo, where their cancer chemopreventive efficacies were found to be very similar to each other [in both methylnitrosourea and dimethylbenz(a)anthracene rat mammary tumor models]. The beta-lyase enzyme is present in many tissues; thus, animals have an ample capacity to metabolize Se-methylselenocysteine systemically. Therefore, Se-methylselenocysteine would be expected to behave like methylseleninic acid if beta-lyase is no longer a limiting factor. Taken together, the present in vitro and in vivo results provide strong evidence in support of our earlier hypothesis that a monomethylated selenium metabolite is important for cancer chemoprevention. Methylseleninic acid could be an excellent tool, especially for molecular mechanism studies in cell culture, and some of these attributes are discussed.