Perspective on Using G lutathione for a W ide Range of Patients w ith Chronic Inflam m atory Response Syndromes

Matthew Lewis, DCIn a clinical setting w here nutritional therapies are offered many providers are seeking strategies to support patients in reducing inflam m ation using lifestyle and nutritional supplementation. Exogenous glutathione

and glutathione precursors use appears to be increasing in the clinical setting for various conditions asso­ciated w ith oxidative stress and glutathione depletion.

This article explores the potential benefits for the use of glutathione or glutathione precursors as a mechanism for reducing inflammation and oxidative stress, with the goal of assisting practitioners in making informed clinical decisions regarding it use.

G LU TA TH IO N E

GSH is the most abundant intracellular antioxidant mol­ecule and protects cells from endogenous and exogenous oxidative stress by donating electrons to ROS.1 The Glutathione redox system is responsible for managing oxida­tive stress . The balance of GSH: GSSG is accomplished through glutathione reductase enzymes. Some of the func­tions of GSH include scavenging of free radicals, xenobiotic detoxification, and the reduction of hydrogen peroxide. GSH is more concentrated intracellularly rather than extracellu- larly. In healthy states, there will be a larger pool of reduced: oxidized glutathione. The reported normal ratios of GSH:GSSH, (Reduced glutathione: Oxidized Glutathione)in a resting state are between 30:1-100:1 in the cytoplasm.2 In a state of oxidative stress levels have been reported at 10:1 and in severe states of oxidative stress as low as 1:1. The ratios of GSH:GSSG are reduced in cancer with various forms of cancer having an predictable reduced ratio.3

DEPLETION O F GSH

As we commonly observe clinically there is almost always multiple routes for depletion of macronutrients, micronutrients, vitamins, and minerals. The same holds true for GSH.

Clinical presentations of infection, cancer, trauma of sur­gery, and malnutrition, can all result in a lowering of the glutathione pool.4 GSH can be depleted due to environmental exposure to cigarettes, synthetic dyes, brominated fire retar­dants,5 mercury, lead, silver, cadmium, zinc and copper.

Prescription medications are conjugated using glutathione, constituting another depleting factor.

GSH is produced intracellularly from cysteine, glycine, and glutamate. Depletion in cysteine is the rate limiting step

for synthesis. Depletion of the raw materials alone can con­tribute to the inability to produce glutathione. This may occur in diets that are low in sulfur vegetables and high in processed foods. Pasteurized and denatured dairy products as opposed to raw dairy products may also be a dietary influence that reduces levels of available glutathione precursors lactoferrin, beta-lactalbumin and serum albumin. Undenatured whey protein contains double bonded cysteine called cystine. Cystine is resistant to stomach acid and are more readably absorbed in the intestine. Once absorbed the rate limiting cys­teine can be used to produce GSH.

Through a process of deduction, when a patient presents with autoimmunity, history of surgery, processed diet, mul­tiple medications, and a mouth full of mercury, the stage has been set for inadequate glutathione levels.

SU PPO R TIN G HEALTHY G LU TA TH IO N E LEVELS

While the evidence is not complete, there appears to be consensus that glutathione is not harmful and evidence of its therapeutic value is continually surfacing.

In some cases where glutathione was studied it has been poorly absorbed into cells and there has been a lack of evi­dence to support increases in GSH due to oral or IV supplementation.6

In the above study one potential limitation was the study of healthy subjects vs. those with chronic disease states that are associated with oxidative stress and the resulting lowering of GSH. The glutathione that was used in this study goes by the trade name Opitac. In the study it was provided orally, but not using liposomes. Studies using GSH in a liposomal form that was provided intravenously demonstrated uptake of GSH into the cells. More studies are needed on the use of orally delivered liposomal glutathione.

GSH also does not appear to stay elevated for long periods following supplementation even when there are positive clin­ical outcomes. Study durations may be too short. Tracking individuals supplementing with GSH over longer periods of time may have different outcomes. Another, possibility is

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Perspective on Using Glutathione

that highly oxidative states would call for rapid cellular uti­lization of GSH and this provides a positive clinical response in the absence of increases in measurable GSH. This appeared to be the case in lung epithelial tissue where fol­lowing nebulized GSH administration markers for lung function and quality of life improved in the absence of decreases in markers for oxidative stress.7

It is established that many common health conditions are chronic in nature and that these conditions are at least in part associated with the many pathways that regulate inflamma­tion and oxidative stress. A variety of chronic patients are seen in the typical nutritional or functional medicine practice, included but not limited to, autoimmunity, heart disease, dia­betes, COPD, neurodegenerative states, and the gray area of undiagnosed unexplained nonspecific inflammation as evi­denced by lab evaluations and physical presentation. The inflammatory mechanisms that damage cells, tissues and organs in these chronic conditions is perpetuated in part due to increased oxidative stress and lowered intracellular glu­tathione pools.8,9

GSH appears to have a role in regulating the immune response during infection, which is a key trigger for autoim­munity. Lower pools of reduced glutathione have been associated with the severity of the autoimmune response, cell apoptosis, and autoantibody production. It appears that increasing intracellular glutathione could have positive impacts on controlling symptoms and progression of tissue destruction associated with autoimmunity.10 The currently available literature provides a positive perspective of the potential therapeutic range for GSH supplementation.

GLUTATHIONE DELIVERY MODELS

When considering utilizing glutathione therapies, there may be value in choosing a direct or indirect path. Direct pathways may include using glutathione or it’s precursors, whereas indirect pathways would be eliciting the restoration of reduced glutathione pools by increasing the enzymatic activity associated with glutathione production and recycling.

Glutathione can be delivered through IV, oral, transder- mal, and nebulized routes. Many functional medicine providers use IV and transdermal routes and report anecdotal clinical success.

The ability to deliver glutathione directly may be chal­lenging. The half- life of glutathione in plasma has been reported to be short. Furthermore, glutathione is broken down into amino acid derivates in plasma, that are then absorbed into the cell and reassembled intracellularly, as process that is impaired in viral states.11 In a clinical setting,

a patient with autoimmunity may present with elevated viral loads.

INDIRECT APPROACHES TO INCREASING GSH

In c reas in g G S H P eroxidase:

GSH peroxidase detoxifies reactive 02 species in the pres­ence of GSH.

Resveratrol is a phytoalexin extracted from the skin of grapes. A phytoalexin is produced by grapes to ward off mold. Resveratrol appears to activate NRF2 which in turn upregulates enzymes associated with glutathione production. This has been demonstrated in vitro to have a positive impact on reducing the oxidative stress associated with cigarette smoke.12

Catechins are flavonoids found in green tea, cocoa, and acai. Catechins have been shown to reduce oxidative stress through Nrf2 stimulation and the subsequent activation of glutathione peroxidases, and glutathione production. This may have a benefit in limiting the colonic damage resulting from oxidative stress in IBS patients.13

Silymarin, a flavonoid from milk thistle increased the expression of glutathione peroxidases, super oxide dismutase and total antioxidant capacity in type 2 diabetic patients com­pared to controls. In a randomized controlled study, a dose of 140 mg three times daily reduced CRP levels in the sily­marin group by twenty six percent.14

Selenium, increases levels of GSH peroxidase. A New Zealand study showed that participants who ate 2 Brazil nuts daily replaced the need for selenomethionine supplementa­tion. Plasma levels of selenium and GSH peroxidase were significantly increased in those given either brazil nuts or selenium, compared to the control.15

PRECURSORS

Precursors to glutathione increase GSH. Various reports conclude that using N-Acetyl Cysteine can increase glu­tathione pools and dampen damaging immune responses. Immune toxicity related to nickel (iNOS activation) was blocked in human immune cells with the addition of NAC.16

In a study of thirty-six SLE patients providing between 2.4 and 4.8 grams of NAC improved lupus disease activity by reducing Mtor activity in T lymphocytes and thereby reducing T cell activity.17

Another animal study in mice, reported that trichloroeth­ylene a ubiquitous industrial waste product found in

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contaminated water, induced autoimmunity, revealed by increased oxidative stress markers and elevated ANA titers. Remarkably, NAC supplementation attenuated not only the TCE-induced oxidative stress, IL-17 release and mRNA expression, but also the markers of autoimmunity, as evident from decreased levels of ANA, anti-dsDNA and anti-Sm antibodies in the sera.18

DIRECT APPROACHES T O GSH SUPPLEMENTATION:

S-Acetylglutathione is an acetylated form of glutathione. S-Acetylglutathione is more stable in the plasma and readily picked up by the cells without having to be broken down into its amino acid derivatives as the case with glutathione. Once in the cells S-Aceytlglutathione is converted to glutathione.19

The administration of S-Acetylglutathione particularly in die face of viral loads appears to be more effective than using GSH. S-Aceytlglutathione was able to decrease mortality induced by HSV-1 in mice.20

In another study examining HIV infected mice, glu­tathione levels were increased using intramuscular injections of S-Aceytl Glutathione, leading to a reduction in infected lymph node weight and a reduction in viral content of the spleen and lymph nodes by 17%.21

Another way to deliver GSH directly is through lipo­somes. A 2017 animal study showed that both in vitro and in vivo delivery of glutathione can be accomplished by using Glutathione disulfide liposomes. Glutathione delivery was done through intravenous injections and into the tumor. The delivery of glutathione into the cell my disulfide liposomes resulted in significant aptosis in cancer cells.22

Oral liposomal applications of glutathione are also being utilized clinically in the absence of complete data. Liposomes have been widely studied and used to deliver various drug preparations.23 Due to the safety of liposomes and GSH it seems a plausible oral route of deliver, even in the face of some uncertainty, give the clinical outcomes are positive.

LABORATORY ASSESSMENT FOR IN F L A M M A T IO N

Before we arrive at measuring GSH, there are many indi­cators of inflammation that can be viewed using commercial lab testing. Patients being seen for chronic conditions may present with a source of inflammation in the GI tract. Stool specimens with elevated SigA or Calprotectin are reliable markers for GI inflammation.24 Each marker for inflamma­tion adds to the clinical confidence levels the practitioner and patient may have in understanding an individual’s inflamma­

tory and oxidative burden.

Common markers can be used as indicators of regression or improvement during treatment with supplemental glu­tathione. Signs of oxidative stress may appear prior to the onset of a specific diagnosis for an autoimmune or met abolic condition. These may include, hsCRP, ESR, Homocysteine, and Uric Acid. While these inflammatory markers are not a direct assessment of glutathione levels, elevated levels are indicative of oxidative stress and may warrant further assess­ment of antioxidant status and guide the clinician in making treatment decisions. Less commonly utilized markers are available for directly measuring reduced glutathione (GSH) and oxidized glutathione (GSSH) and amino acid levels.25

As described earlier In healthy states, there will be a larger pool of reduced: oxidized glutathione. The reported normal ratios of GSH:GSSH in a resting state are as high as 100:1. In a state of oxidative stress levels have been reported at 10:1 and in severe states of oxidative stress as low as 1:1.

Amino acid testing can be performed to assess for the rate limiting GSH amino acid cysteine and evaluate reduced and oxidized glutathione. Some of these tests are available in commercial labs. Health Diagnostic Research Institute and Genova labs provide assessments of GSH, GSSG, GSH per­oxidase, amino acid, and antioxidant status.

C O N C L U S IO N

Many of the studies relating to Glutathione indicate a pos­itive direction for the increased utilization of GSH and GSH precursors in the clinical setting for support in reducing the chronic inflammatory response. While it is difficult to find conclusive results as to absorption, utilization, and effects, the safety of GSH use appears to be consistent throughout the literature. (26), (27) In the authors opinion, judicial use of GSH, with monitoring of clinical indicators and laboratory tests, will assist the practitioner in understanding the potential gains for patients with chronic inflammatory stress responses, while continued research will provide more clues on how and when to best utilize GSH clinically.

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27. Randomized, single blind, controlled trial of inhaled glu­tathione vs placebo in patients with cystic fibrosis. CalabreseC, Tosco A,, s.l. : Journal Cystic Fibrosis, 2015. Mar;14(2):203-10. doi: 10.1016/j.jcf.2014.09.014. Epub 2014 Nov 4.

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