Generation of superoxide from reaction of 3H-1,2-dithiole-3-thione with thiols: implications for dithiolethione chemoprotection
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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.
KeywordsEPR Superoxide D3T Oxygen consumption Thiols
Antioxidant response element
Electron paramagnetic resonance
Mitogen-activated protein kinases
Reactive oxygen species
This work was supported in part by NIH grant HL71190 (Y. L.). M. A. T. was supported by NIH grants ES03760, ES03819 and ES08078.
- 2.Jacobson LP, Zhang BC, Zhu YR, Wang JB, Wu Y, Zhang QN, Yu LY, Qian GS, Kuang SY, Li YF, Fang X, Zarba A, Chen B, Enger C, Davidson NE, Gorman MB, Gordon GB, Prochaska HJ, Egner PA, Groopman JD, Munoz A, Helzlsouer KJ, Kensler TW (1997) Oltipraz chemoprevention trial in Qidong, People’s Republic of China: study design and clinical outcomes. Cancer Epidemiol Biomarkers Prev 6:257–265PubMedGoogle Scholar
- 6.Li Y, Cao Z, Trush MA (2004) Chemical carcinogenesis and mutagenesis. In: F Barile (ed) Clinical toxicology: principles and mechanisms. CRC Press, Florida, pp 359–376Google Scholar
- 7.Kim W, Gates KS (1997) 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. Chem Res Toxicol 10:296–301PubMedCrossRefGoogle Scholar
- 13.Frejaville C, Karoui H, Tuccio B, Le Moigne F, Culcasi M, Pietri S, Lauricella R, Tordo P (1995) 5-(Diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide: a new efficient phosphorylated nitrone for the in vitro and in vivo spin trapping of oxygen-centered radicals. J Med Chem 38:258–265PubMedCrossRefGoogle Scholar
- 17.Timmins GS, Liu KJ, Bechara EJ, Kotake Y, Swartz HM (1999) Trapping of free radicals with direct in vivo EPR detection: a comparison of 5,5-dimethyl-1-pyrroline-N-oxide and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide as spin traps for HO· and SO4 ·-. Free Radic Biol Med 27:329–333PubMedCrossRefGoogle Scholar