By early February 2006, the World Health Organization had reported 165 human cases of H5N1 influenza since December 2003, with 88 fatalities. However, the avian H5N1 influenza virus apparently is not yet efficiently transmitted between humans. Though a near-term possibility of a global H5N1 influenza pandemic remains, currently there is no vaccine or anti-viral drug that is proven to be safe and effective in preventing or treating H5N1 influenza in humans. There is thus a compelling public interest in developing alternative prophylaxis and treatment strategies for H5N1 influenza, which would need to address the complex pathogenesis of H5N1 influenza that is responsible for its apparently unusually high virulence. The authors present here a significant body of medical and scientific evidence to support the prophylactic use of a carefully designed nutritional supplement formulation that may antagonize the major pathogenic processes of H5N1 influenza in humans. Through several independently-mediated mechanisms, the formulations may: (a) degrade H5N1 virulence by directly affecting the virus itself, (b) inhibit H5N1 viral replication by maintaining cellular redox equilibrium in host cells, (c) inhibit H5N1 replication by a blockade of the nuclear-cytoplasmic translocation of the viral ribonucleoproteins and reduced expression of late viral proteins related to the inhibition of protein kinase C activity and its dependent pathways, (d) down-regulate activation and proliferation of proinflammatory cytokines in respiratory epithelial cells and macrophages that are implicated in the pathogenesis of H5N1 influenza, and (e) protect the lungs and other vital organs from virus- and cytokine-induced oxidative stress by supplying and maintaining sufficient levels of exogenous and endogenous antioxidants. Key mediators in these processes include selenium, vitamin E, NAC/glutathione, resveratrol, and quercetin. Taken prophylactically, and throughout the duration and recovery of an H5N1 infection, the nutritional supplement formula may aid humans infected with H5N1 influenza to survive with a reduced likelihood of major complications, and may provide a relatively low-cost strategy for individuals as well as government, public-health, medical, health-insurance, and corporate organizations to prepare more prudently for an H5N1 pandemic. Some evidence also indicates that the supplement formulation may be effective as an adjunctive to H5N1 vaccine and anti-viral treatments, and should be tested as such.

STUDY OBJECTIVES: To assess the impact of inhaled, buffered reduced glutathione (GSH) on clinical indicators of cystic fibrosis (CF) pathophysiology. DESIGN AND PATIENTS: A randomized, double-blind, placebo-controlled pilot study was conducted over an 8-week period. Nineteen subjects, age 6 to 19 years, with CF status documented by positive sweat chloride test results (> 60 mEq/L) were recruited for the trial. After matching on age and sex, 10 patients were randomly assigned to the treatment group and 9 patients to the placebo group. Primary outcomes were FEV1, FVC, forced expiratory flow at 25 to 75% of vital capacity, and peak flow; secondary outcomes were body mass index, 6-min walk distance, and self-reported cough frequency, mucus production/viscosity/color, wellness, improvement, and stamina. INTERVENTIONS AND ANALYSIS: Treatment was buffered GSH, and placebo was sodium chloride with a hint of quinine. The total daily dose of buffered GSH was approximately 66 mg/kg of body weight, and the total daily dose of placebo was approximately 15 mg/kg of body weight (quinine, 25 to 30 microg/kg). Doses were distributed across four inhalation sessions per day and spaced 3- to 4-h apart. General linear mixed models were used to analyze the data. The final sample size was nine subjects in the treatment group and seven subjects in the placebo group. RESULTS: Mean change for peak flow was -6.5 L/min for the placebo group and +33.7 L/min for the GSH group (p = 0.04), and self-reported average improvement on a scale from 1 to 5 (1 being much worse and 5 being much better) was 2.8 for placebo and 4.7 for GSH (p = 0.004). Of the 13 primary and secondary outcomes examined, 11 outcomes favored the treatment group over the placebo group (p = 0.002), indicating a general tendency of improvement in the GSH group. No adverse events in the treatment group were noted. CONCLUSION: This pilot study indicates the promise of nebulized buffered GSH to ameliorate CF disease, and longer, larger, and improved studies of inhaled GSH are warranted.

OBJECTIVE: To explain the role of oxidative stress in the pathology of celiac disease. DESIGN AND METHODS: The activities of antioxidant enzymes and the levels of glutathione and lipid hydroperoxides were measured in the samples of small intestinal biopsies from 39 children with different forms of the disease and in 19 control subjects. RESULTS: The activities of analyzed enzymes varied significantly between the examined groups. An increase in the activities of superoxide dismutase was observed in patients with active and silent celiac disease, while the activities of glutathione peroxidase and glutathione reductase and the glutathione content were significantly reduced. The level of lipid hydroperoxides was significantly elevated in these groups. CONCLUSIONS: Oxidative stress is an important factor in the pathogenesis of celiac disease. The antioxidant capacity of celiac patients is significantly reduced, mostly by a depletion of glutathione. Natural antioxidants and appropriate dietary supplements could be important complements to the classic therapy of celiac disease.

We have employed a model in vitro system for iron-peroxide-catalyzed oxidation of porphyrinogens to investigate the potential role of glutathione (GSH) in trace metal-induced porphyrias. GSH strongly attenuates porphyrinogen oxidation at biologically relevant concentrations in a dose-dependent manner. Porphyrinogenic trace metals reduce the effectiveness of GSH as a porphyrinogen antioxidant, leading to significantly higher rates of porphyrinogen oxidation to porphyrins. These observations may, in part, underlie the etiology of porphyrinurias induced during prolonged trace metal exposures.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) of nonmutant superoxide dismutase (SOD) type may be caused by toxicity of the reduced glutathione (GSH) precursors glutamate and cysteine, and sulfite (a metabolite of cysteine), which accumulate when one or more of the enzymes needed for GSH synthesis are defective. OBJECTIVES: A case is examined where the patient exhibited elevated sulfur on a hair mineral analysis, elevated blood cysteine, positive urine sulfite, elevated urine glutamate, and low whole blood GSH. During the time when strict dietary and supplement measures normalized the patient's whole blood GSH, blood cysteine, and urine sulfite, the patient did not experience additional physical decline. The possible causes of abnormalities of the patient's laboratory test results, as well as the nutrition measures used to normalize them, are discussed in relationship to the functions and importance of cysteine, sulfite, and glutamate in glutathione metabolism in ALS. CONCLUSIONS: Since elevated plasma cysteine has been reported in other ALS patients, sulfite and cysteine toxicity may be involved in other cases of ALS. Patients with ALS with nonmutant-SOD should be tested for sulfite toxicity, cysteine, glutamate and GSH levels, and whether they have low levels of GSH metabolism enzymes. Since glutamate metabolism appears to be inhibited by sulfite, research on the effect of sulfite on glutamate levels in patients with ALS should be pursued. Life might be prolonged in those patients with ALS with sulfite toxicity by closely monitoring the blood cysteine and urine sulfite levels and minimizing their dietary intake, as well as increasing GSH by using sublingual GSH. A long-term solution might be found through research to determine methods to increase GSH synthesis without using sulfur-containing supplements that may add to the cysteine and sulfite toxicity.

We have previously shown chronic immune activation and enhanced generation of reactive oxygen species in common variable immunodeficiency (CVI). In the present study, we examined levels of glutathione, the dominant intracellular thiol, that play an important protective role against oxidative and inflammatory stress in plasma and in monocytes and lymphocyte subsets in 20 CVI patients and in 16 healthy controls. CD4+ lymphocytes from CVI patients had significantly lower levels of both total and reduced glutathione as well as a lower ratio of reduced to total glutathione compared with healthy controls. This decrease in glutathione levels in CD4+ lymphocytes was most pronounced in the CD45RA+ subset. Plasma levels of total glutathione were also significantly decreased in CVI. In contrast, monocytes from CVI patients exhibited increased levels of both total and reduced glutathione compared with blood donor monocytes. CVI patients had significantly raised serum levels of tumor necrosis factor alpha (TNF alpha) and TNF alpha concentration was strongly associated with glutathione depletion in CD4+ lymphocytes. Furthermore, the lowest levels of both total and reduced glutathione were found in a subgroup of CVI patients characterized by persistent immune activation in vivo, decreased numbers of CD4+ lymphocytes in peripheral blood, and splenomegaly. Finally, supplementation of cell cultures with glutathione-monoethyl ester did significantly enhance interleukin-2 production from peripheral blood mononuclear cells in CVI patients. These glutathione abnormalities in CVI indicate increased oxidative stress, particularly in CD4+ lymphocytes, and intracellular depletion of reduced glutathione of the demonstrated magnitude may have profound implications for CD4+ lymphocyte function and the immunodeficiency in CVI.

Oxaliplatin, a platinum-based anti-cancer drug, induces peripheral neuropathy as a side effect and causes cold hyperalgesia in cancer patients receiving anti-cancer chemotherapy. In oxaliplatin-treated mice, aluminum was accumulated in the dorsal root ganglia (DRG), and accumulated aluminum in DRG or other organs aggravated oxaliplatin-induced neuropathic pain. To investigate whether aluminum oxalate, which is the compound of aluminum and oxaliplatin, might be the peripheral neuropathy inducer, the withdrawal responses of mice to coldness, the expression of transient receptor potential ankyrin 1 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays in DRG were analyzed in mice administered with aluminum oxalate. In addition, the concentrations of aluminum in aluminum oxalate-treated mice were significantly increased compared to those of mice treated with aluminum chloride. To alleviate neuropathic pain, glutathione (GSH), known as an antioxidant and a metal chelator, was injected into oxaliplatin-treated mice. The concentrations of aluminum in the DRG were decreased by the chelation action of GSH. Taken together, behavioral and molecular analyses also supported that aluminum accumulation on the DRG might be a factor for neuropathic pain. This result also suggested that the aluminum chelation by GSH can provide an alleviatory remedy of neuropathic pain for cancer patients with oxaliplatin-induced neuropathic pain.

Methyl mercury (MeHg) is highly neurotoxic and may lead to numerous neurodegenerative disorders. In this study, we investigated the role of glutathione (GSH) and reactive oxygen species (ROS) in MeHg-induced neurotoxicity, using primary cell cultures of cerebellar neurons and astrocytes. To evaluate the effect of GSH on MeHg-induced cytotoxicity, ROS and GSH were measured using the fluorescent indicators chloro methyl derivative of di-chloro di-hydro fluorescein diacetate (CMH(2)DCFDA) and monochlorobimane (MCB). Cell-associated MeHg was measured with (14)C-radiolabeled MeHg. Mitochondrial dehydrogenase activity was detected by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. MTT timeline study was also performed to evaluate the effects of both the concentration and duration of MeHg exposure. The intracellular GSH content was modified by pretreatment with N-acetyl cysteine (NAC) or di-ethyl maleate (DEM) for 12 h. Treatment with 5 microM MeHg for 30 min led to significant (p<0.05) increase in ROS and reduction (p<0.001) in GSH content. Depletion of intracellular GSH by DEM further increased the generation of MeHg-induced ROS in both cell cultures. Conversely, NAC supplementation increased intracellular GSH and provided protection against MeHg-induced oxidative stress in both cell cultures. MTT studies also confirmed the efficacy of NAC supplementation in attenuating MeHg-induced cytotoxicity. The cell-associated MeHg was significantly (p<0.02) increased after DEM treatment. In summary, depletion of GSH increases MeHg accumulation and enhances MeHg-induced oxidative stress, and conversely, supplementation with GSH precursor protects against MeHg exposure in vitro.

The activity of glutathione peroxidase (GSH-Px) as well as the activities of other antioxidative enzymes: CuZn superoxide dismutase (CuZn SOD), catalase (CAT), glutathione reductase (GR) in erythrocytes, as well as the activity of plasma glutathione transferase (GST), and the plasma content of vitamins E and C were evaluated in 35 sporadic amyotrophic lateral sclerosis (sALS) patients. The results revealed significantly decreased activity of both GSH-Px and CuZn SOD in sALS patients compared with the control. These data showed that a disturbed oxidative/antioxidative balance in sALS patients exists not only in motoneurons but also in the blood. The effect of exogenously administered selenium (Se), antioxidants, amino acids, a Ca2+ channel blocker such as nimodipine, and their combination in Alsamin was evaluated by screening parameter levels after 9 weeks of treatment. Only the use of all components together enhanced the activity of GSH-Px and the amount of vitamin E in sALS patients. Judging by the results of clinical trials, this treatment slowed the course of the disease.

Highly active antiretroviral therapy (HAART) has significantly improved the prognosis of HIV-1-infected patients but is associated with significant side effects such as diabetes, atherosclerosis, and cardiovascular complications. Oxidative stress can disrupt endothelial homeostasis by dysregulating the balance between pro- and antiatherogenic factors. We hypothesized that chronic exposure to HAART results in endothelial oxidative stress and activation of mononuclear cell recruitment, an early event in atherosclerosis. We studied the effects of HAART drug combinations, consisting of zidovudine, a nucleoside reverse transcriptase inhibitor; efavirenz, a nonnucleoside reverse transcriptase inhibitor; and either of the two protease inhibitors (PIs), indinavir or nelfinavir, on human aortic endothelial cells (HAECs) by monitoring the following parameters: (1) generation of reactive oxygen species (ROS), (2) mono-nuclear cell (Jurkat or U-937) adhesion, and (3) expression of cell adhesion molecules (CAMs). HAART exposure increased ROS formation in HAECs. Exposure to PIs alone and in HAART combinations increased mononuclear cell adhesion to HAECs in a concentration-dependent manner. Mononuclear cell adhesion to HAART-exposed HAECs was significantly enhanced following acute (24-h) exposure to the inflammatory cytokines, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and was suppressed by the antioxidants N-ace-tylcysteine and glutathione. Exposure to HAART increased intercellular adhesion molecule-1 (ICAM-1) gene expression and concomitant exposure to TNF-alpha further increased ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and endothelial-leukocyte adhesion molecule cell surface protein levels. These studies indicate that chronic HAART exposure increases oxidative stress in endothelial cells and induces mononuclear cell recruitment, which may eventually precipitate the cardiovascular diseases observed in HIV-1+ individuals on antiretroviral therapy.

CFTR mutation, which causes cystic fibrosis (CF), has also recently been identified as causing glutathione system dysfunction and systemic deficiency of reduced glutathione (GSH). Such dysfunction and deficiency regarding GSH may contribute to the pathophysiology of CF. We followed 13 patients (age range 1-27 years) with cystic fibrosis who were using a regimen of reduced glutathione (GSH), including oral glutathione and inhaled buffered glutathione in an uncontrolled, observational study. Dosage ranged from 66-148 mg/kg/day in divided doses, and the term examined was the initial 5.5 months of GSH use (45 days of incrementally adjusted dose, plus 4 months of use at full dosage). Baseline and post-measurements of FEV1 percent predicted, BMI percentile, and weight percentile were noted, in addition to bacterial status and pulmonary exacerbations. Significant improvement in the following clinical parameters was observed: average improvement in FEV1 percent predicted (N=10) was 5.8 percentage points (p<0.0001), average weight percentile (N=13) increased 8.6 points (p<0.001), BMI percentile (N=11) improved on average 1.22 points (p<0.001). All patients improved in FEV1 and BMI, if measured in their case; 12 of 13 patients improved in weight percentile. Positive sputum cultures of bacteria in 11 patients declined from 13 to 5 (p<0.03) with sputum cultures of Pseudomonas aeruginosa becoming negative in 4 of 5 patients previously culturing PA, including two of three patients chronically infected with PA as determined by antibody status. Use of a daily GSH regimen appears to be associated in CF patients with significant improvement in lung function and weight, and a significant decline in bacteria cultured in this uncontrolled study. These findings bear further clinical investigation in larger, randomized, controlled studies.

The influence of gamma radiation on basal compared to activation-dependent Ca(2+) influx in human lymphocytes was investigated. A new quantitative fluorescence technique termed differential ratiometric fluorescence spectroscopy (DRFS) was employed. DRFS facilitated the real-time detection of changes in fluorescence in experimental and control cell samples simultaneously, enabling the resolution of acute moderate changes ( congruent with10-30%) in Ca(2+) (manganese) influx after exposure to ionizing radiation and other oxidant interventions. Exposure to radiation inhibited thapsigargin-stimulated store-operated Ca(2+) influx but not basal Ca(2+) influx in Jurkat T cells and human peripheral blood lymphocytes. The response of store-operated Ca(2+) influx to gamma radiation was dependent on dose between 5 and 40 Gy and was inhibited by preincubation with the Ca(2+) channel blocker Ni(2+), as determined with Jurkat T cells. Elevation of the intracellular concentration of glutathione significantly reduced the inhibition of Ca(2+) influx by gamma radiation. Similar to radiation, both the superoxide anion-generating xanthine/xanthine oxidase system and hydrogen peroxide inhibited thapsigargin-stimulated Ca(2+) influx in Jurkat T cells, and this inhibition was reversed in the presence of the antioxidant N-acetyl-l-cysteine. In conclusion, (1) ionizing radiation inhibited store-operated Ca(2+) entry in human lymphocytes, (2) the sensitivity of Ca(2+) influx to radiation was strictly dependent on depletion of Ca(2+) stores, and (3) glutathione protected against the inhibition of store-operated Ca(2+) entry by gamma radiation.

RATIONALE: The toxicity of H2S has been attributed to its ability to inhibit cytochrome c oxidase in a similar manner to HCN. However, the successful use of methemoglobin for the treatment of HCN poisoning was not successful for H2S poisonings even though the ferric heme group of methemoglobin scavenges H2S. Thus, we speculated that other mechanisms contribute to H2S induced cytotoxicity. Experimental procedure. Hepatocyte isolation and viability and enzyme activities were measured as described by Moldeus et al. (1978), and Steen et al. (2001). RESULTS: Incubation of isolated hepatocytes with NaHS solutions (a H2S source) resulted in glutathione (GSH) depletion. Moreover, GSH depletion was also observed in TRIS-HCl buffer (pH 6.0) treated with NaHS. Several ferric chelators (desferoxamime and DETAPAC) and antioxidant enzymes (superoxide dismutase [SOD] and catalase) prevented cell-free and hepatocyte GSH depletion. GSH-depleted hepatocytes were very susceptible to NaHS cytotoxicity, indicating that GSH detoxified NaHS or H2S in cells. Cytotoxicity was also partly prevented by desferoxamine and DETAPC, but it was increased by ferric EDTA or EDTA. Cell-free oxygen consumption experiments in TRIS-HCl buffer showed that NaHS autoxidation formed hydrogen peroxide and was prevented by DETAPC but increased by EDTA. We hypothesize that H2S can reduce intracellular bound ferric iron to form unbound ferrous iron, which activates iron. Additionally, H2S can increase the hepatocyte formation of reactive oxygen species (ROS) (known to occur with electron transport chain). H2S cytotoxicity therefore also involves a reactive sulfur species, which depletes GSH and activates oxygen to form ROS.

While mushrooms are the highest dietary source for the unique sulfur-containing antioxidant ergothioneine, little is known regarding levels of the major biological antioxidant glutathione. Thus, our objectives were to determine and compare levels of glutathione, as well as ergothioneine, in different species of mushrooms. Glutathione levels varied>20-fold (0.11-2.41mg/gdw) with some varieties having higher levels than reported for other foods. Ergothioneine levels also varied widely (0.15-7.27mg/gdw) and were highly correlated with those of glutathione (r=0.62, P<0.001). Both antioxidants were more concentrated in pileus than stipe tissues in selected mushrooms species. Agaricus bisporus harvested during the third cropping flush contained higher levels of ergothioneine and glutathione compared to the first flush, possibly as a response to increased oxidative stress. This study demonstrated that certain mushroom species are high in glutathione and ergothioneine and should be considered an excellent dietary source of these important antioxidants.

Free radical mediated damage has been reported to contribute significantly towards low survival (5-10%) of grafted dopaminergic neurons, post transplantation. In the present study, an attempt has been made to explore the neuroprotective potential of the combination of two major antioxidants ascorbic acid (AA) and glutathione (GSH) on ventral mesencephalic cells (VMC) and nigral dopamine (DA) neurons when co-transplanted together with VMC in rat model of Parkinson's disease (PD). GSH and AA have been reported to act co-operatively in the conditions of oxidative stress thereby helping in maintaining the cellular GSH/GSSG redox status. Functional recovery was assessed 12 weeks post transplantation, where a significant restoration (p<0.001) in d-amphetamine induced circling behavior (62%), spontaneous locomotor activity (SLA; 64%), dopamine-D2 receptor binding (63%), dopamine (65%) and 3,4-dihydroxy phenyl acetic acid (DOPAC) level (64%) was observed in co-transplanted animals as compared to lesioned and VMC alone grafted rats. VMC and GSH+AA co-transplanted animals exhibited a significantly higher surviving TH-immunoreactive (TH-ir) neurons number (p<0.01), TH-ir fibers outgrowth (p<0.05) in striatal graft and TH-ir neurons in substantia nigra pars compacta (SNpc) (p<0.01), as compared to VMC alone transplanted rats. An attempt was made to further confirm our in vivo observations through in vitro experiments where following in vitro exposure to 6-OHDA, a higher cell survival (p<0.01), TH-ir cell counts (p<0.001) and DA and DOPAC levels (p<0.01) were also observed in 8-day-old VMC culture in presence of GSH+AA as compared to VMC cultured in absence of antioxidants. The results suggest that GSH+AA when co-transplanted with VMC provide higher restoration probably by increasing the survival of grafted VMC and simultaneously supporting nigral TH-immunopositive neurons in rat model of PD.

Free radical mediated damage has been reported to contribute significantly towards low survival (5-10%) of grafted dopaminergic neurons, post transplantation. In the present study, an attempt has been made to explore the neuroprotective potential of the combination of two major antioxidants ascorbic acid (AA) and glutathione (GSH) on ventral mesencephalic cells (VMC) and nigral dopamine (DA) neurons when co-transplanted together with VMC in rat model of Parkinson's disease (PD). GSH and AA have been reported to act co-operatively in the conditions of oxidative stress thereby helping in maintaining the cellular GSH/GSSG redox status. Functional recovery was assessed 12 weeks post transplantation, where a significant restoration (p<0.001) in d-amphetamine induced circling behavior (62%), spontaneous locomotor activity (SLA; 64%), dopamine-D2 receptor binding (63%), dopamine (65%) and 3,4-dihydroxy phenyl acetic acid (DOPAC) level (64%) was observed in co-transplanted animals as compared to lesioned and VMC alone grafted rats. VMC and GSH+AA co-transplanted animals exhibited a significantly higher surviving TH-immunoreactive (TH-ir) neurons number (p<0.01), TH-ir fibers outgrowth (p<0.05) in striatal graft and TH-ir neurons in substantia nigra pars compacta (SNpc) (p<0.01), as compared to VMC alone transplanted rats. An attempt was made to further confirm our in vivo observations through in vitro experiments where following in vitro exposure to 6-OHDA, a higher cell survival (p<0.01), TH-ir cell counts (p<0.001) and DA and DOPAC levels (p<0.01) were also observed in 8-day-old VMC culture in presence of GSH+AA as compared to VMC cultured in absence of antioxidants. The results suggest that GSH+AA when co-transplanted with VMC provide higher restoration probably by increasing the survival of grafted VMC and simultaneously supporting nigral TH-immunopositive neurons in rat model of PD.

Though the cause of cystic fibrosis (CF) pathology is understood to be the mutation of the CFTR protein, it has been difficult to trace the exact mechanisms by which the pathology arises and progresses from the mutation. Recent research findings have noted that the CFTR channel is not only permeant to chloride anions, but other, larger organic anions, including reduced glutathione (GSH). This explains the longstanding finding of extracellular GSH deficit and dramatically reduced extracellular GSH:GSSG (glutathione disulfide) ratio found to be chronic and progressive in CF patients. Given the vital role of GSH as an antioxidant, a mucolytic, and a regulator of inflammation, immune response, and cell viability via its redox status in the human body, it is reasonable to hypothesize that this condition plays some role in the pathogenesis of CF. This hypothesis is advanced by comparing the literature on pathological phenomena associated with GSH deficiency to the literature documenting CF pathology, with striking similarities noted. Several puzzling hallmarks of CF pathology, including reduced exhaled NO, exaggerated inflammation with decreased immunocompetence, increased mucus viscoelasticity, and lack of appropriate apoptosis by infected epithelial cells, are better understood when abnormal GSH transport from epithelia (those without anion channels redundant to the CFTR at the apical surface) is added as an additional explanatory factor. Such epithelia should have normal levels of total glutathione (though perhaps with diminished GSH:GSSG ratio in the cytosol), but impaired GSH transport due to CFTR mutation should lead to progressive extracellular deficit of both total glutathione and GSH, and, hypothetically, GSH:GSSG ratio alteration or even total glutathione deficit in cells with redundant anion channels, such as leukocytes, lymphocytes, erythrocytes, and hepatocytes. Therapeutic implications, including alternative methods of GSH augmentation, are discussed.