Submitted on September 15, 2006
Accepted on March 4, 2007
A role for CFTR in the elevation of glutathione in the lung by oral glutathione administration
Chirag Kariya1, Heather Leitner1, Elysia Min2, Christiaan van Heeckeren3, Anna van Heeckeren3, and Brian J. Day4*
1 Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado, United States
2 Medicine, National Jewish Medical and Research Center, Denver, Colorado, United States
3 Pediatrics, Case Western Reserve University, Cleveland, Ohio, United States
4 Division Occupational Environmental Health, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado, 80206, United States; Medicine, University of Colorado Health Sciences Center, Denver, Colorado, United States; Immunology, University of Colorado Health Sciences Center, Denver, Colorado, United States; Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado, United States
* To whom correspondence should be addressed. E-mail: dayb{at}njc.org.
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is the only 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. GSH levels peaked at 30 minutes in the plasma and 60 minutes in the lung, ELF and BAL cells after oral GSH dosing. GSH treatment produced a selective GSH increase in all lung compartments. Oral GSSG treatment (300mg/kg) resulted in a smaller increase of GSH levels. To evaluate the role of CFTR, Cftr KO and gut corrected Cftr KO-Tg mice were given an oral bolus dose of GSH (300 mg/kg) and compared to wild type mice. There was a 2-fold increase in plasma and lung, a 5-fold increase in ELF, and a 3-fold increase in BAL cell GSH levels at 60 minutes in wild type mice, however GSH levels only increased by 40% in the plasma, 60% in the lung, 50% in the ELF, and 2-fold 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.
