Kim W, Gates K S
Department of Chemistry, University of Missouri-Columbia 65211, USA.
Chem Res Toxicol. 1997 Mar;10(3):296-301. doi: 10.1021/tx9601667.
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 property, in addition to electrophilicity, that may play a role in the induction of protective phase II enzymes by this promising class of anticarcinogens.
1,2 - 二硫杂环戊烯 - 3 - 硫酮是一类重要的抗癌剂，可选择性地诱导细胞产生具有化学保护作用的II期解毒酶。确定抗癌剂中负责这种酶诱导的化学性质很重要。此前，1,2 - 二硫杂环戊烯 - 3 - 硫酮诱导II期酶的能力被归因于它们的亲电特性。我们在此报告，抗癌性的1,2 - 二硫杂环戊烯 - 3 - 硫酮，奥替普拉（4 - 甲基 - 5 - 吡嗪基 - 3H - 1,2 - 二硫杂环戊烯 - 3 - 硫酮，1）和3H - 1,2 - 二硫杂环戊烯 - 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。使用监测DNA切割的基于质粒的测定方法，我们发现1和2在微摩尔浓度下能有效切割DNA，并且这种切割可通过去除分子氧、添加自由基清除剂（甘露醇、甲醇、乙醇和二甲基亚砜）、偶然痕量金属的螯合剂以及过氧化物破坏酶过氧化氢酶来抑制。综合来看，我们的数据表明，在这些反应中，分子氧转化为过氧化物物种，该物种经历痕量金属催化的芬顿型反应以产生活性氧自由基从而切割DNA。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，除亲电性外，1,2 - 二硫杂环戊烯 - 3 - 硫酮产生活性氧应被视为第二种化学性质，这可能在这类有前景的抗癌剂诱导保护性II期酶中发挥作用。
