Am. J. Respir. Cell Mol. Biol., Vol 17, No. 2, Aug 1997, 227-234.
Induction of cystine transport and other stress proteins by disulfiram: effects on glutathione levels in cultured cells
SM Deneke, PH Harford, KY Lee, CF Deneke, SE Wright and SG Jenkinson
Department of Medicine, The University of Texas Health Science Center at San Antonio, 78284-7885, USA.
Disulfiram (Antabuse) (DSF) has been reported to protect rats and other
animals from the effects of hyperbaric hyperoxia at 4 to 6 ATA
(atmospheres). In contrast, DSF and diethyldithiocarbamate (DDC), its
metabolite, accelerate the toxic effects in rats of 100% oxygen at 1 to 2
ATA. We have examined the effects of DSF and DDC on glutathione (GSH)
levels in bovine pulmonary artery endothelial cells and Chinese hamster
ovary cells. Increases in intracellular GSH occurred 8 to 24 h after
addition of DSF to the culture media. These increases in intracellular GSH
were associated with increases in the rate of uptake of cystine into the
cells. DDC was a less effective inducer of cystine uptake and increased
intracellular GSH levels than was DSF. At the concentrations used, neither
DDC nor DSF caused significant decreases in intracellular superoxide
dismutase levels. Exogenous sulfhydryl compounds including GSH and cysteine
partially blocked the induction of cystine transport by DSF or DDC,
suggesting that the induction might be mediated through a sulfhydryl
reaction between DSF and some cellular components. The increases in GSH in
the cultured cells were not significant by 4 h of exposure. In contrast,
other stress proteins including heme oxygenase are induced by 2 to 4 h
after DSF addition. In previously reported in vivo studies, DSF treatment
protected against hyperbaric oxygen damage after as little as 1 to 4 h
pre-exposure. This suggests that effects of DSF exposure other than GSH
augmentation may be responsible for the protective effects seen in vivo.
