Evidence for thiol-dependent production of oxygen radicals by 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (Oltipraz) and 3H-1,2-dithiole-3-thione: Possible relevance to the anticarcinogenic properties of 1,2-dithiole-3-thiones
Evidence for thiol-dependent production of oxygen radicals by 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (Oltipraz) and 3H-1,2-dithiole-3-thione: Possible relevance to the anticarcinogenic properties of 1,2-dithiole-3-thiones
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DOI：
10.1021/tx9601667
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发表时间：
1997-03-01
影响因子：
4.1
通讯作者：
Gates, KS
中科院分区：
文献类型：
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作者：
Kim, W;Gates, KS
1,2-二硫-3-硫酮是一类重要的抗癌物质，可选择性地诱导细胞产生化学保护II期解毒酶。重要的是要确定负责这种酶诱导的抗癌物质的化学性质。以前，1,2-二硫-3-硫酮诱导II相酶的能力被归因于它们的亲电性。我们在这里报道了抗癌的1,2-二硫基-3-硫酮，oltipraz（4-甲基-5-pyrazinyl- 3h -1,2-二硫基-3-硫酮，1）和3h -1,2-二硫基-3-硫酮(2)，与硫醇（包括生物硫醇谷胱甘肽）一起介导分子氧向活性氧自由基的转化。利用一种基于质粒的检测DNA切割的方法，我们发现1和2在微摩尔浓度下可以有效地切割DNA，并且这种切割可以通过去除分子氧、添加自由基清除剂（甘露醇、甲醇、乙醇和二甲亚砜）、外来微量金属螯合剂和过氧化氢酶来抑制。综上所述，我们的数据表明，在这些反应中，分子氧被转化为过氧化物，经过微量金属催化的芬顿型反应，产生切割DNA的氧自由基。已知活性氧能够调节哺乳动物细胞中的基因表达；因此，我们的研究表明，除了亲电性之外，1,2-二硫-3-硫酮产生的氧自由基应该被认为是第二种化学推进机制，它可能在这类有前途的抗癌物质诱导保护性II期酶的过程中发挥作用。
1,2-Dithiole-3-thiones are an important class of anticarcinogens that selectively induce cellular production of chemoprotective phase II detoxification enzymes. It is important to identify chemical properties of anticarcinogens that are responsible for this enzyme induction. Previously, the ability of 1,2-dithiole-3-thiones to induce phase II enzymes has been attributed to their electrophilic character. We report here that the anticarcinogenic 1,2-dithiole-3-thiones, oltipraz (4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione, 1) and 3H-1,2-dithiole-3-thione (2), in conjunction with thiols, including the biological thiol glutathione, mediate the conversion of molecular oxygen to reactive oxygen radicals. Using a plasmid-based assay that monitors DNA cleavage, we find that 1 and 2, at micromolar concentrations, efficiently cleave DNA and that this cleavage can be suppressed by removal of molecular oxygen, addition of radical scavenging agents (mannitol, methanol, ethanol, and dimethyl sulfoxide), chelators of adventitious trace metals, and the peroxide-destroying enzyme catalase. Taken together, our data suggest that, in these reactions, molecular oxygen is converted to a peroxide species that undergoes a trace metal-catalyzed, Fenton-type reaction to generate oxygen radicals that cleave DNA. Reactive oxygen species are known to be capable of modulating gene expression in mammalian cells; thus, our studies indicate that oxygen radical production by 1,2-dithiole-3-thiones should be considered as a second chemical propel ty, in addition to electrophilicity, that may play a role in the induction of protective phase II enzymes by this promising class of anticarcinogens.