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.

Transcriptional Activation of the UDP-Glucuronosyltransferase1A7 Gene in Rat Liver by Aryl Hydrocarbon Receptor Ligands and Oltipraz

“…An identical pattern of mRNA regulation is observed for UGT1A6 (3,9,11,12), the better known PAH-inducible UGT with activity toward 4-nitrophenol and other simple phenols but not benzo(a)pyrene phenols (13,14). Because PAHs and oltipraz are known to induce transcription of other metabolizing enzymes by mechanisms involving the arylhydrocarbon receptor and/or oxidative stress (15)(16)(17), our findings suggest that UGT1A6 and UGT1A7 may each be under the control of cis elements implicated in these responses, i.e. the xenobiotic response element (XRE) for arylhydrocarbon receptor mediated effects and the antioxidant response element (ARE) for oxidative stress-associated effects.…”

Increased bioactivation of dihaloalkanes in rat liver due to induction of class Theta glutathione S-transferase T1-1

“…All these inducers are metabolized by cytochrome P-450 and there is an expectation that enzyme induction may involve the generation of reactive oxygen species as a consequence of poor coupling between P-450 and the reductase [6]. Indeed, the requirement for the generation of the superoxide anion by oltipraz in order for it to act as an inducing agent has been discussed recently [42].…”

Medicinal Chemistry: Insights into the Development of Novel H2S Donors

“…It is possible that the elevated GSH contributes much more than H 2 S in those pharmaceutical benefits. Moreover, it is known that DTTs can participate in other Scheme 5 The structures of NOSH-1, AP39, and PEG-ADT biological reactions such as electrophilic reactions (Talalay et al 1988) and conversion of molecular oxygen to reactive oxygen radicals (Kim and Gates 1997). These possibilities should also be taken into consideration.…”