There is a remarkable molecule circulating through your bloodstream: glutathione. Not only is it a virtual powerhouse of antioxidant defense and enzyme production, but it’s also fundamental to a wide range of metabolic and regulatory functions. So essential is this substance to maintaining your health that deficiency states have been linked to a multitude of diseases, even aging. Let’s take a look at glutathione, its vital roles and the importance of maintaining optimal levels of this key nutrient.
Glutathione’s Chemistry underlies its Biological Functions
The following is a short primer on glutathione biochemistry, provided in order to fully grasp its physiological significance. Please bear with the following paragraphs, because a wealth of information crucial to your health follows.
Glutathione is a tripeptide synthesized from the amino acids glutamine, cysteine and glycine and is intimately involved in maintaining the antioxidant status of cells and tissues. Remember from Chemistry 101 (if it’s not too unpleasant!) that oxidation and reduction are complementary chemical reactions described as the loss or gain of electrons, respectively, by a molecule, atom, or ion. In addition to glutathione’s relatively high concentration within cells, the presence of the sulfhydryl (–SH) group on the cysteine portion of the molecule is at the foundation of its powerful antioxidant capacity 1234 ? electrons of this sulfur-containing group are readily donated to quench, or reduce, damaging free radicals and reactive oxygen species (ROS), which are highly reactive, unstable, and deleterious to the body. Glutathione exists within cells in its reduced form, denoted GHS, but in the process of neutralizing ROS, it becomes oxidized to glutathione disulfide, GSSG. Redox is chemical shorthand for reduction-oxidation reaction, and in biological systems, the term redox ratio is used to describe the balance of reduced to oxidized metabolites, in this case GSH/GSSG.
Source: pubchem.ncbi.nlm.nih.gov
Now that we have digested this information, we’re ready to appreciate these two gems of information: first, the ratio of reduced to oxidized glutathione, GSH/GSSG, within the cell is fundamental to cell function and viability and is under tight regulation4 and second, GSH/GSSG is the major redox pair that determines antioxidant capacity in animal cells. 1356. There in a nutshell is the basis of glutathione’s vast biological significance. Under normal physiological conditions this ratio should be greater than 10.18 However, in response to oxidative stress, a dangerous imbalance between the production and removal of ROS, glutathione concentrations can plummet,13568 shifting the GSH/GSSG redox toward the damaging oxidizing state. We will see below the link between increased oxidation and disease and then later how we can positively impact our glutathione redox ratio toward a more healthy balance. First, let’s expand our discussion of glutathione’s functions in the body.
Biological Roles of Glutathione
We have just seen that the reduced to oxidized glutathione ratio plays a crucial role in the maintenance and regulation of the antioxidant status of the cell. This characteristic underlies glutathione’s importance in a multitude of physiological processes.
Glutathione is used as a substrate for certain enzymes that detoxify ROS generated from free radical attack on DNA, proteins and other biomolecules, as well as other enzymes that complex glutathione with potentially harmful substances such as estrogens, and xenobiotics (substances foreign to the body) in order to detoxify them.134
Besides the antioxidant defense glutathione provides as an enzyme substrate, it also acts as an endogenous (originating within the body) antioxidant by directly quenching oxygen free radicals.134 Interestingly, it also helps reduce and then recycle oxidized forms of other antioxidants such as ascorbate (vitamin C) and alpha-tocopherol (a form of vitamin E).4
In addition, glutathione is also a major transport form of cysteine in the body1 and the biochemical foundation of the P450 detoxification system in the liver, kidneys, and other organs.4
And besides maintaining the redox balance of the cell, glutathione plays an important role in many other regulatory pathways including signal transduction, gene expression, DNA and protein synthesis, cell proliferation, apoptosis, cytokine production and immune response, and preserving mitochondrial function.126
Glutathione Depletion Linked to Disease States
By now, it’s clear that glutathione is crucial to regulating and neutralizing deleterious oxidative processes, among other essential roles in the body. Medical experts agree that a deficiency of glutathione (and corresponding decrease in the redox ratio) contributes to increased oxidation and is implicated in aging and the onset and progression of many diseases.12346
Many oxidative stressors can deplete glutathione levels: ultraviolet and other radiation, viral infections, environmental toxins, household chemicals, heavy metals, surgery, inflammation, burns, septic shock, and overuse of certain pharmaceuticals such as acetaminophen4. Diminished glutathione levels can also be a result of limited synthesis due to fasting or inadequate protein or amino acid intake.14
There is a growing and almost limitless range of human diseases associated with glutathione deficiency and resulting oxidative stress:1246
- hemolytic anemia
- neuropathy, myopathy
- HIV/AIDS
- cirrhosis, viral hepatitis
- chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma
- Crohn’s Disease, gastritis, duodenal ulcer, pancreatitis
- heart attack, coronary artery disease
- Wilson’s Disease
- diabetes
- neurodegenerative diseases including Alzheimer’s and Parkinson’s
- Cystic fibrosis
- cancer
- stroke
- inflammation
- seizure
Even the aging process itself is associated with impaired glutathione metabolism.1246
Supplementation to Improve Glutathione Status
You may very well be asking by this point, “But what can I do about it? How can I optimize my body’s antioxidant capacity?” With so many disorders associated with oxidative stress as a result of lowered glutathione levels, nutritional strategies to restore a more favorable redox ratio may offer therapeutic potential in treating the abundance of human diseases mentioned above, and may even provide an effective anti-aging strategy.
Several substances have been shown to increase glutathione synthesis in vivo such as n-acetyl cysteine (an orally bioavailable source of cysteine, sufficient quantities of which are necessary for glutathione synthesis); the amino acids glutamine, glycine and taurine; alpha-lipoic acid, s-adenosylmethionine (SAM-e), and ascorbate.14
And research continues on glutathione itself as a therapeutic agent. Although there is conflicting data in the medical literature, a growing number of studies have demonstrated that oral administration of glutathione can directly increase plasma and tissue glutathione concentrations and exert positive physiological benefits.
In a study evaluating plasma glutathione concentration in rats after glutathione dosing as either a liquid bolus or mixed in feed, researchers observed a substantial increase in plasma glutathione which peaked at 90 to 120 minutes after administration and remained high for over three hours.8
At Louisiana State University Medical Center, in a similar investigation examining dietary intake of glutathione in mice, concentrations in plasma more than doubled within 30 minutes, “consistent with a rapid flux of glutathione from the intestinal lumen to plasma,” and also increased in lung tissue over the same time period.9 These results are consistent with another pharmacokinetic profile (time course study) in mice in which glutathione levels peaked at 30 minutes in plasma and 60 minutes in lung tissue after oral administration of a bolus dose.10 The Louisiana State University authors also reported that dietary intake increased glutathione concentrations in several tissues besides lung, but only after glutathione -depletion by a chemical agent.9
But this last result was later challenged by Italian researchers who found that glutathione levels increased substantially in many organs after oral glutathione administration, whether animals had first been treated with a glutathione -depleting agent or not: “significant increases in glutathione levels were found in jejunum, lung, heart, liver and brain after oral glutathione administration” to rats that had not been treated with a glutathione -depleting chemical and “in all organs, except liver, when glutathione was administered to rats previously glutathione -depleted.” Increases were due to uptake by intact glutathione, or by its degradation and subsequent re-synthesis, or both mechanisms, depending on the organ studied.11
And in a fascinating 2002 study, oral glutathione supplementation was found to suppress oxidative stress in vivo and potentially treat symptoms of diabetes. This is strong evidence that glutathione is indeed effective orally. Diabetic rats fed a glutathione-supplemented diet demonstrated decreases in lipid peroxidation as measured by a marker of oxidative stress, as well as improvements in diabetic neuropathy and kidney dysfunction, both of which are diabetic complications linked to oxidative damage.3
Conclusion
We have learned that glutathione is fundamental to myriad physiological processes ? perhaps most importantly, the regulation of the antioxidant status cells and tissues. Alterations in glutathione metabolism and resulting oxidative stress can lead to the plethora of disease states that we have examined, as well as accelerate the aging process itself. Fortunately, several studies have reported that targeted glutathione supplementation may potentially restore this key nutrient to more optimal levels to ameliorate and possibly prevent pathological conditions associated with lowered glutathione status. Continuing research will undoubtedly expand our knowledge of this unique and remarkable nutrient.
Note: Glutathione use during chemotherapy is not recommended, unless otherwise directed by a physician.
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References
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- Ueno Y, Kizaki M, Nakagiri R, Kamiya T, Sumi H, Osawa T. Dietary glutathione protects rats from diabetic nephropathy and neuropathy. J Nutr. 2002 May;132(5):897-900.
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- Hagen TM, Wierzbicka GT, Sillau AH, Bowman BB, Jones DP. Bioavailability of dietary glutathione: effect on plasma concentration. Am J Physiol. 1990 Oct;259(4 Pt 1):G524-9.
- Aw TY, Wierzbicka G, Jones DP. Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact. 1991;80(1):89-97.
- Kariya C, Leitner H, Min E, van Heeckeren C, van Heeckeren A, Day BJ. A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration. Am J Physiol Lung Cell Mol Physiol. 2007 Jun;292(6):L1590-7.
- Favilli F, Marraccini P, Iantomasi T, Vincenzini MT. Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters. Br J Nutr. 1997 Aug;78(2):293-300.