Reduced glutathione (GSH) is well recognised for its role as a key antioxidant in the body and for its function as an endogenous detoxifier, helping remove toxins and potential carcinogens.
An additional factor, that is often overlooked, is the degree to which inflammation can deplete glutathione (GSH), which in turn contributes to the persistence of an inflammatory state. Research shows that reductions in GSH lead to increased levels of pro-inflammatory mediators and inflammatory potential. Consequently, GSH levels and function should be considered when addressing chronic inflammatory disease states.
Oxidative stress is a driver of inflammation. Increases in reactive oxygen species (ROS) and reactive nitrogen species (RNS) activate transcription factors (e.g. NFkB) and the release of pro-inflammatory cytokines, e.g. tumour necrosis factor (TNF) -alpha.[2,3] The subsequent initiation of inflammatory processes sees the development of further oxidative stress. If unresolved, GSH is depleted, worsening the oxidative and inflammatory environment. As a result a destructive, self-sustaining and auto-amplifying disease state develops.
GSH and Inflammatory Bowel Disease (IBD)
The cellular damage that leads to chronic intestinal inflammation is not completely understood, however oxidative stress is believed to be a potential triggering factor.[3,4] This may be provoked by a range of insults including bacterial antigens, environmental factors and/or chemical agents.
As the vicious cycle of inflammation and oxidative stress persists, gut barrier function is impaired contributing to systemic inflammatory stress and more widespread symptoms. More so, GSH depletion is noted in IBD and should be considered when designing a treatment protocol for these patients.
N-acetyl-cysteine (NAC), once deacetylated, becomes cysteine which is a cellular precursor of GSH. Preliminary evidence has shown NAC supplementation reduces inflammation, alleviates oxidative stress, improves energy status and ameliorates tissue damage in the intestines. These benefits are believed to be achieved through NAC helping to maintain intracellular concentrations of GSH.
GSH and Lung Health
Alterations in alveolar and lung GSH metabolism are widely recognised as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. Preliminary research investigating the influence of local oxidative stress in pulmonary disease found that by increasing intracellular GSH in lung cells, the release of pro-inflammatory cytokines and chemokines is attenuated via decreased NGkB activation.
In these airway diseases it is believed that an altered ratio of GSH to oxidised Glutathione (GSSG) in the epithelial lining fluid and airway cells is what leads to the release of pro-inflammatory cytokines, e.g. interleukin (IL) -8. These imbalances are also possibly implicated in airway hyper-responsiveness and dysfunction in asthma.
Oral use of NAC may be implicated in chronic lung conditions as not only does it contribute antioxidant benefits but is also used as a mucolytic agent, reducing mucous viscosity and mucociliary clearance.
GSH and Neurological Health
GSH in the brain is a known neuromodulator, neurotransmitter and enabler of neuron survival.
Recently, many neurodegenerative and psychological (e.g. major depression, bipolar disorder and schizophrenia) conditions have been associated with inflammation, oxidative stress, mitochondrial dysfunction, toxicity and compromised integrity at both the gastrointestinal tract and blood brain barrier, all of which can be linked to GSH depletion.
Depression, anxiety disorders and cognitive decline have all been linked with decreases in expression of certain nerve growth factors, e.g. brain derived neurotropic factor (BDNF). BDNF promoted neuronal survival and regeneration in areas of the brain such as those involved in emotion, behaviour, learning and memory. A loss of BDNF therefore results in reduced activity in such areas of the brain and subsequent mood and cognitive symptoms.
Key factors linked to reduced BDNF expression include inflammation and oxidative stress from ROS and RNS, each associated with GSH depletion.
Not surprisingly, interventions which aim to increase intracellular GSH concentrations (e.g. NAC[1,9,15] and curcumin,[1,16]) and reduce oxidative stress and/or inflammation (e.g. omega-3 from fish ) have shown benefit in addressing the symptoms of specific mood disorders.
To function as an antioxidant, GSH requires a group of enzymes known as the glutathione peroxidases. These are selenoproteins, meaning they are selenium-dependent. Once GSH functions as an antioxidant, it becomes GSSG; it requires reduction by glutathione reductase, which is riboflavin (Vitamin B2) dependent and NADP (derived from Vitamin B3) is also required.
The glutathione molecule is a tripeptide consisting of three amino acids, glutamine, cysteine and glycine. Cysteine is the limiting factor for glutathione synthesis. Cysteine acts as an antioxidant in its own right, being converted to cystine in this process. Cystine then requires reduction back into cysteine in order to continue its antioxidant function and/or to be involved in the synthesis of glutathione. Alpha-lipioc acid is known to increase intracellular glutathione through its role in assisting the reduction of cystine to cysteine, thus enhancing its availability for glutathione manufacture within the cells.
Vitamin D status should also be considered where oxidative stress and inflammation are present. Not only does Vitamin D play a direct role in immune modulation, but a study on healthy adults showed serum 25(OH)D concentrations to be independently associated with major plasma redox systems (measured by reduced and oxidised glutathione and cysteine levels). This suggests that Vitamin D status may be involved in oxidative stress-related pathophysiology.
Glutathione and the Diet
Certain foods contains levels of the actual glutathione tripeptide, whilst others are rich in the amino acid building blocks (e.g. cysteine) and/or antioxidants (e.g. alpha-lipioc acid) which facilitate the maintenance of intracellular GSH levels. Specific foods and herbs will also increase the activity of specific enzymes (e.g. glutathione s-transferase) that support glutathione's detoxification functions. The below listed foods provide one or a combination of these benefits and are thus highly recommended as part of an anti-inflammatory diet (assuming there are no identified intolerances).
- Vegetables (e.g. asparagus, capsicum, carrot, onion, broccoli/broccoli sprout, cabbage, avocado, spinach, garlic)
- Fruits (e.g. apples, oranges, peaches, bananas, melon)
- Whey Powder (manufacturing processes must ensure retention of intact proteins)
- Turmeric (containing curcumin)
In the past, glutathione bioavailibility has been questioned. More recent research however has demonstrated that orally ingested GSH does in fact achieve significant increases in intracellular GSH levels.
One recent trial of 54 people administered doses of 250mg or 1000mg or placebo to human subjects for a 6 month period. GSH levels were measured at 1, 3 and 6 months. Both GSH groups achieved dose-dependent increases in GSH at various sites including the blood, erythrocytes, lymphocytes and buccal cells. Both groups were also observed to have reductions in oxidative stress, as indicated by decreases in the oxidised to reduced glutathione ratio in whole blood. After just 3 months natural killer cell cytotoxicity was increased more and two-fold in the higher dose group.
This research suggests that oral glutathione supplementation can be a useful adjunct to treatment protocols for patients presenting with disease states associated with GSH depletion.
Management of illnesses associated with chronic inflammation may benefit from dietary and supplemental approaches that address oxidative stress and mitigate GSH depletions. Reduced glutathione itself is a useful supplement at doses between 250mg and 1000mg, whilst N-acetyl-cysteine, curcumin, alpha-lipoic acid, fish oil, selenium, B vitamins and vitamin D can also be considered.
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