A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is the only known apical glutathione (GSH) transporter in the lung. The purpose of these studies was to determine whether oral GSH or glutathione disulfide (GSSG) treatment could increase lung epithelial lining fluid (ELF) GSH levels and whether CFTR plays a role in this process. The pharmacokinetic profile of an oral bolus dose of GSH (300 mg/kg) was determined in mice. Plasma, ELF, bronchoalveolar lavage (BAL) cells, and lung tissue were analyzed for GSH content. There was a rapid elevation in the GSH levels that peaked at 30 min in the plasma and 60 min in the lung, ELF, and BAL cells after oral GSH dosing. Oral GSH treatment produced a selective increase in the reduced and active form of GSH in all lung compartments examined. Oral GSSG treatment (300 mg/kg) resulted in a smaller increase of GSH levels. To evaluate the role of CFTR in this process, Cftr knockout (KO) mice and gut-corrected Cftr KO-transgenic (Tg) mice were given an oral bolus dose of GSH (300 mg/kg) and compared with wild-type mice for changes in GSH levels in plasma, lung, ELF, and BAL cells. There was a twofold increase in plasma, a twofold increase in lung, a fivefold increase in ELF, and a threefold increase in BAL cell GSH levels at 60 min in wild-type mice; however, GSH levels only increased by 40% in the plasma, 60% in the lung, 50% in the ELF, and twofold in the BAL cells within the gut-corrected Cftr KO-Tg mice. No change in GSH levels was observed in the uncorrected Cftr KO mice. These studies suggest that CFTR plays an important role in GSH uptake from the diet and transport processes in the lung.

Improvement in clinical markers in CF patients using a reduced glutathione regimen: An uncontrolled, observational study

“…Because these previous studies focused on lung function parameters, clinical indicators concerning the growth failure typical of pancreatic insufficient CF patients were not examined in detail. In fact, there was some reason to believe that oral glutathione would be of little use in the treatment of CF patients [7]. Nevertheless, these results show that significant weight gain is also associated with use of this GSH regimen.…”

“…Since the discovery that the CFTR channel was the major mechanism of GSH efflux into the extracellular milieu of the lung from lung epithelial cells and that this efflux was severely compromised in cystic fibrosis (CF) [1][2][3][4][5][6], resulting in glutathione system dysfunction and systemic deficiency of reduced glutathione (GSH) in CF, researchers have begun to explore what role glutathione system dysfunction plays in cystic fibrosis disease. Not only have in vitro studies proven useful in the development of new hypotheses in this regard [7][8][9][10][11][12][13][14][15][16][17], but several clinical trials of GSH or GSH precursors such as NAC have resulted in improvement in clinically-relevant markers in CF patients [18][19][20][21][22][23].…”

Oxidative Stress Due to ( R )-Styrene Oxide Exposure and The Role of Antioxidants in Non-Swiss Albino (NSA) Mice

“…Another study showed that NAC (2.5 mmol/kg) ip 1 h prior to acetaminophen (5 mmol/kg) treatment was effective in preventing increases in plasma alanine aminotransferase (ALT) activities (Gomez et al, 1994). Kariya et al (2007) found that 1 h after an oral dose of 300 mg/kg GSH, GSH levels in lung tissue increased twofold. A study by Vina et al (1989) showed that administration of GSH orally was sufficient to increase GSH levels in fasted rats, as well as in mice treated with the GSH-depleting agent diethyl maleate.…”

Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

“…A number of investigators have shown that CFTR facilitates glutathione efflux into luminal fluids, either directly by serving as a glutathione channel (33,36) or indirectly by affecting the activity of other glutathione transporters (19), with the luminal glutathione serving an antioxidant function. Previous studies have demonstrated that glutathione efflux is reduced in cells lacking a functional CFTR (19,20), and reduced levels of GSH have been reported in extracellular bronchoalveolar lavage fluid from both CF patients (7,47) and mice (8,30,57).…”