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

Departments of 1 Medicine and 2 Immunology, National Jewish Medical and Research Center, Departments of 3 Medicine, 4 Immunology, and 5 Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado; and 6 Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio Submitted 15 September 2006 ; accepted in final form 4 March 2007 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. nutrition; transport; high-performance liquid chromatography; mice; cystic fibrosis; antioxidant; cystic fibrosis transmembrane conductance regulator Address for reprint requests and other correspondence: B. J. Day, National Jewish Medical and Research Center, A439, 1400 Jackson St., Denver, CO 80206 (e-mail: dayb{at}njc.org )