Chemoprotective 3H-1,2-dithiole-3-thione induces antioxidant genes in vivo.
Several 1,2-dithiole-3-thiones are potent inhibitors of chemical-induced tumors in multiple tissues. Chemoprotection by 1, 2-dithiole-3-thiones has been associated with induction of detoxication enzymes, although several studies suggest that additional mechanisms may be involved. In this study, we examined the induction of hepatic antioxidant genes in rats treated with 3H-1, 2-dithiole-3-thione (D3T). After a 24 h D3T treatment, a 2.4-fold increase in catalase mRNA was observed, which was accompanied by a 1. 5-fold increase in catalase protein expression and a 2.3-fold increase in catalase activity. D3T also mediated 2.9-, 5.9-, and 3. 7-fold increases in the 1.0, 3.0, and 4.0 kb mRNA species of manganese superoxide dismutase (MnSOD), respectively. The induction of MnSOD mRNA by D3T was coincident with 1.7-fold and 4.6-fold increases in MnSOD protein and enzyme activity, respectively. Induction of gamma-glutamylcysteine synthetase mRNA by D3T was accompanied by an increase in glutathione levels. Nuclear run-on assays provided evidence that D3T enhances the transcription rate from MnSOD, catalase, and gamma-glutamylcysteine synthetase. In support of this view, D3T also activated an MnSOD promoter-reporter construct in transiently transfected HepG2 cells. In light of observations that antioxidant enzyme regulation may be altered during carcinogenesis, induction of these genes could provide a potentially important mechanism of action of chemoprotective 1, 2-dithiole-3-thiones.
Otieno
M A
MA
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Kensler
T W
TW
Guyton
K Z
KZ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013871:Thiones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000975:Antioxidants; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; D002374:Catalase; D013482:Superoxide Dismutase; D005721:Glutamate-Cysteine Ligase; C049325:1,2-dithiol-3-thione