Abstract
3H-1,2-Dithiole-3-thione (D3T), a potent member of dithiolethiones, induces phase 2 enzymes by activating an Nrf2/Keap1-dependent signaling pathway. It was proposed that interaction between D3T and two adjacent sulfhydryl groups of Keap1 might cause dissociation of Keap1 from Nrf2, leading to Nrf2 activation. This study was undertaken to investigate the reactions between D3T and thiols, including the dithiol compound, dithiothreitol (DTT), and the monothiol, glutathione (GSH). We reported here that under physiologically relevant conditions incubation of D3T with DTT caused remarkable oxygen consumption, indicating a redox reaction between D3T and the dithiol molecule. Incubation of D3T with GSH also led to oxygen consumption, but to a less extent. Electron paramagnetic resonance (EPR) studies showed that the redox reaction between D3T and DTT generated superoxide. Superoxide was also formed from the redox reaction of D3T with GSH. These findings demonstrate that D3T reacts with thiols, particularly a dithiol, generating superoxide, which may provide a mechanistic explanation for induction of Nrf2-dependent phase 2 enzymes by D3T.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use
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Chemoprevention / methods
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Dithiothreitol / pharmacology
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Dose-Response Relationship, Drug
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Glutathione / chemistry
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Glutathione / pharmacology
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Oxidation-Reduction
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Oxygen Consumption / drug effects
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Reactive Oxygen Species / chemical synthesis
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Spin Trapping / methods
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Sulfhydryl Compounds / chemistry*
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Sulfhydryl Compounds / pharmacokinetics*
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Superoxide Dismutase / antagonists & inhibitors
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Superoxides / chemical synthesis*
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Thioinosine / analogs & derivatives
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Thioinosine / chemistry
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Thioinosine / metabolism
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Thiones / chemistry*
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Thiones / pharmacokinetics*
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Thiones / therapeutic use*
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Thiophenes / chemistry*
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Thiophenes / pharmacokinetics*
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Thiophenes / therapeutic use*
Substances
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(diethoxyphosphoryl)-5-methylpyrroline N-oxide
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Antineoplastic Agents
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Pyrroles
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Reactive Oxygen Species
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Sulfhydryl Compounds
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Thiones
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Thiophenes
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Superoxides
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Thioinosine
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Superoxide Dismutase
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Glutathione
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4-nitrobenzylthioinosine
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Dithiothreitol
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1,2-dithiol-3-thione