Oltipraz stimulates the transcription of the manganese superoxide dismutase gene in rat hepatocytes.
Oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) (OPZ) is recognized as a potent chemoprotective agent against chemical-induced carcinogenesis in several animal models and is thought to act mainly by inducing phase II conjugating together with inhibiting phase I detoxication enzymes. The present study was undertaken to determine whether oltipraz can also influence expression of genes encoding antioxidant enzymes. In rat hepatocytes in primary culture, this compound was found to selectively induce the transcription of the manganese superoxide dismutase (Mn-SOD) gene while it had no effect on copper/zinc-SOD and glutathione peroxidase genes. Oltipraz increased Mn-SOD gene expression in a time- and dose-dependent manner by 2- to 3-fold and enhanced the binding activity of the nuclear factor kappa B within 30 min. Moreover, the increase in Mn-SOD gene transcription was associated with a 2- to 3-fold increase of free malondialdehyde and conjugated dienes, two markers of lipid peroxidation, an index of oxidative stress. These results suggest that in rat hepatocytes, oltipraz induced a production of reactive oxygen species that probably acted as second messengers in order to trigger the transcription of many genes. Such a mechanism of action of OPZ and other dithiolethiones would account for the broad spectrum of action of these anticarcinogenic compounds.
Antras-Ferry
J
J
Unité INSERM 456 et Laboratoire de Biologie Cellulaire et Végétale, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, France.
Mahéo
K
K
Chevanne
M
M
Dubos
M P
MP
Morel
F
F
Guillouzo
A
A
Cillard
P
P
Cillard
J
J
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000201:enzymology*; D008297:Male; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D013871:Thiones; D013876:Thiophenes; D014158:Transcription, Genetic / Q000187:drug effects*
D016588:Anticarcinogenic Agents; D011719:Pyrazines; D017382:Reactive Oxygen Species; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D013482:Superoxide Dismutase