title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Missouri-Columbia 65211, USA.
authors.forename: W
authors.initials: W
authors.lastname: Kim
authors.forename: K S
authors.initials: KS
authors.lastname: Gates
mesh_terms: D000693:Anaerobiosis; D016588:Anticarcinogenic Agents / Q000737:chemistry* / Q000494:pharmacology; D002021:Buffers; D002614:Chelating Agents / Q000737:chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004249:DNA Damage; D004591:Electrophoresis, Polyacrylamide Gel; D016166:Free Radical Scavengers / Q000737:chemistry; D005609:Free Radicals / Q000737:chemistry; D010957:Plasmids / Q000737:chemistry; D011719:Pyrazines / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013871:Thiones / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; D002021:Buffers; D002614:Chelating Agents; D016166:Free Radical Scavengers; D005609:Free Radicals; D011719:Pyrazines; D013438:Sulfhydryl Compounds; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; C049325:1,2-dithiol-3-thione