Phorone (diisopropylidene acetone), a glutathione depletor, decreases rat glucocorticoid receptor binding in vivo.
The exact mechanism by which carcinogens and tumor promoters act on the glucocorticoid receptor system in vivo is not known. Based on earlier studies that sulfhydryl-reducing agents stabilize glucocorticoid receptor binding in vitro, some workers have postulated that endogenous reducing factors may be important for glucocorticoid receptor function in vivo. To test whether glutathione (GSH) may serve this purpose, we investigated the effects of phorone, an agent that partially depletes intracellular GSH, on the hepatic cytosolic glucocorticoid receptor (GRc) binding characteristics in intact and 7-10 day adrenalectomized (ADX) adult female Sprague-Dawley rats. Biochemical analysis revealed that a single treatment of phorone (300 mg/kg) to both intact and ADX rats significantly decreased the liver GSH concentration (70-90% of control levels) as well as the GRc maximum binding concentration (30% of control levels). The decrease in GSH levels preceded the reduction in GRc maximum binding concentrations; both effects were reversible after 24 h of treatment. The phorone-mediated decrease of GSH levels was maximum at doses greater than 75 mg/kg, whereas GRc maximum binding concentrations in vivo appeared dose dependent up to 400 mg/kg. Pretreatment with phorone or the carcinogens mirex and 3-methylcholanthrene significantly decreases GRc binding and nuclear uptake in vivo, as well as diminishes intracellular cytosolic GSH levels. Although a temporal relationship between the GSH levels and the GRc maximum binding concentrations in vivo was observed, there was no quantitative relationship between these two parameters based on our phorone dose-response and the carcinogen pretreatment data. Our findings suggest that during the early phases of carcinogenesis, the hepatocellular GSH does not play a direct role upon the biochemical action of certain carcinogens and tumor promoters on the glucocorticoid receptor binding in the liver.
Sunahara
G I
GI
Nestlé Research Centre, NESTEC Ltd., Vers-chez-les-Blanc, Lausanne, Switzerland.
Chiesa
A
A
D000818:Animals; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019803:Glutathione Disulfide; D007659:Ketones / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008748:Methylcholanthrene / Q000494:pharmacology; D008917:Mirex / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D012997:Solvents / Q000494:pharmacology
D007659:Ketones; D011965:Receptors, Glucocorticoid; D012997:Solvents; D008748:Methylcholanthrene; D003907:Dexamethasone; C018637:phorone; D005978:Glutathione; D019803:Glutathione Disulfide; D008917:Mirex