July 2015 Issue

Antioxidants: The Power of Glutathione
By Andrea N. Giancoli, MPH, RD
Today's Dietitian
Vol. 17 No. 7 P. 56

Experts provide answers to important questions about this master antioxidant.

Hailed for its antioxidant power, glutathione is the latest compound crowding the dietary supplement shelves. Indeed, the Natural Medicines Comprehensive Database lists hundreds of products sold in the United States containing glutathione, including chewing gum, powders, and lotions.1

But what is glutathione, and how vital is it to human health? Today's Dietitian answers the most common questions about this powerful antioxidant so nutrition professionals can better counsel clients and patients.

What Is Glutathione?
Glutathione is a tripeptide composed of the nonessential amino acids glutamate, cysteine, and glycine. It's ubiquitous in the body, found in all living cells of animals, plants, and even bacteria, and it's an endogenous compound with every cell having the capability of producing it. Thus, glutathione isn't considered an essential nutrient.

"Glutathione is one of the most important molecules in all of biology," says glutathione researcher John P. Richie, Jr, PhD, a professor of public health sciences and pharmacology at Penn State University College of Medicine. Glutathione is probably best known for its protective abilities as a powerful antioxidant. It also protects the body against toxins and has anticarcinogenic properties. It further plays an important role in regulating cell function based on oxidation-reduction conditions inside the cell, Richie says.

Moreover, glutathione is crucial for maintaining a healthy immune system. More specifically, Richie says "the ability of your T-cells and lymphocytes to respond when faced with a challenge depends on whether there's an adequate amount of glutathione in your cells for immune regulation."

As an endogenous compound, glutathione stands out from the more familiar antioxidants, such as selenium, vitamin C, and vitamin E, which must come from the diet. "What really sets it apart isn't just the fact that all of our cells have the capacity to make it," Richie says. "It's the whole enzyme system built up around it. When other antioxidants do their job as antioxidants, they get oxidized, and in doing so they can become a problem," he adds. "In the case of glutathione, the oxidized product of glutathione is actually quite safe. One of the reasons why it's so safe is there's an enzyme that can turn it right back into glutathione. This enzyme is in all cells."

How Is Glutathione Measured in the Body?
Glutathione levels aren't measured routinely outside of a research setting. However, Richie estimates that average levels in healthy people are about 30 mg/dL and can range from 20 to 45 mg/dL. And glutathione levels can ebb and flow. "There are fluctuations over the course of the day in certain tissues like the liver," Richie says. "If you haven't eaten for a while, your liver levels of glutathione will go down quite substantially, upwards of 40% to 50% after just six hours."

Lisa Cimperman, MS, RDN, LD, a spokesperson for the Academy of Nutrition and Dietetics, says that the ratio of oxidized to reduced glutathione may be more clinically significant than simply looking at levels. Glutathione is a reducing agent, which means it can give up an electron to stabilize and inactivate cell-damaging reactive free radical molecules that lead to disease. Once glutathione gives up an electron, it's in an oxidized form and must revert back to its reduced form once again to quench free radicals. "Selenium plays an important role in converting glutathione back to its reduced form," Cimperman says.

"We want most of the glutathione to be in the reduced form," she adds. "Typically, people have about 90% of the glutathione in that reduced form and 10% in the oxidized form. During a very severe inflammatory state, we can see an increase in that oxidized form of glutathione. That may mean the system is being taxed more than normal. And that makes sense because in inflammation you have more production of free radicals," which may jeopardize the body's ability to effectively neutralize them, leading to increased disease risk.

What Impacts Glutathione Levels, and Are There Consequences for Having Reduced Levels?
Environmental toxins, alcohol intake, and tobacco use, as well as genetic differences, can impact glutathione levels, Richie says. "Some people have a gene that isn't quite as active as others, so they're less able to make glutathione." One may not experience symptoms on a day-to-day basis, but Richie says that many "diseases and disorders are associated with low glutathione levels, such as HIV and diabetes,2 and neurodegenerative diseases such as Parkinson's are associated with glutathione depletion specifically in certain regions of the brain."3

Should Individuals Try to Boost Glutathione Levels, and If So, How?
Fruits and vegetables are the best sources of glutathione. However, there's disagreement on whether exogenous glutathione can survive the digestive process intact and allow for intestinal absorption, or if it undergoes hydrolyzation down to its constituent amino acids. "There are lots of proteins and peptides that make it through the stomach and get into the intestine and are absorbed," Richie says. "It appears that glutathione is one of those.4 There's a lot of data in laboratory animal models where people found that when you added glutathione in the diet you could impact increased levels in tissues. In animal models, it gets in and gets in rapidly.5,6 They've even identified the transporter protein that's responsible for transporting it to the intestines."6

To date, the same findings haven't been demonstrated in humans. Richie led a May 2014 study published in the European Journal of Nutrition and found that adults taking 250 mg or 1,000 mg of supplemental glutathione per day over a six-month period increased their glutathione levels for both doses.7 To put this into perspective, a small apple contains less than 5 mg of glutathione and one-half cup of asparagus contains about 26 mg.8

But the question of whether or not there's a need to try to boost glutathione levels in the body still remains. There isn't enough evidence currently to answer this question, but Richie theorizes that "based on the research that's been done to date, one would expect higher glutathione levels to bolster the protective systems in the body.9-13 You should be better protected from all sorts of toxic insults and oxidants, and that should put you at lower risk of toxicities and diseases related to oxidative stress. Just about every disease has been linked to oxidative stress in some way or another, and that includes cancer and heart disease."

Richie cautions that more research must be done before health care professionals can conclude whether raising glutathione levels will lower disease risk. "Nobody's ever done a long-term study on glutathione supplementation on health and disease. We're just learning now what we need to do in order to do that."

Is It Safe to Take Supplemental Glutathione?
The Natural Medicines Comprehensive Database categorizes glutathione as "possibly safe" when taken orally, inhaled, administered intramuscularly, or intravenously. But it recommends pregnant or nursing women avoid glutathione supplementation due to a lack of safety evidence. According to the Natural Medicines Comprehensive Database, there are no reports of adverse reactions or interactions with drugs, foods, herbs, or supplements. Acetaminophen and alcohol, however, can deplete glutathione levels, possibly reducing its therapeutic effect. Asthmatics should avoid inhalable glutathione as it can cause bronchospasm.

Cimperman is cautious when it comes to recommending supplementation from a clinical standpoint. "We really don't know how exogenous supplementation is going to impact endogenous glutathione production. Will the body then decrease its own production of glutathione? We don't know how increasing glutathione is going to affect disease, inflammation, or infection—if at all. These are all things the research hasn't shown or clarified."

Richie agrees that it's too soon to make these determinations, but he says he's optimistic since the literature suggests that people who have higher endogenous glutathione levels may be healthier than those who have lower levels. "But I don't think we've reached a point yet where we can point to a normal range and indicate if you're lower than this amount, then you may be at greater [disease] risk, and that you should be doing something to increase your levels."

— Andrea N. Giancoli, MPH, RD, is a nutrition communications consultant in Hermosa Beach, California.

References
1. Glutathione. Natural Medicines Comprehensive Database website. http://naturaldatabase.therapeuticresearch.com/nd/Search.aspx?cs=CEPDA~
MBR&s=ND&pt=100&id=717&ds=&name=GLUTATHIONE&searchid=51481522. Updated March 6, 2015. Accessed April 30, 2015.

2. Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomed Pharmacother. 2003;57(3-4):145-155.

3. Maher P. The effects of stress and aging on glutathione metabolism. Ageing Res Rev. 2005;4(2):288-314.

4. Hagen TM, Wierzbicka GT, Sillau AH, Bowman BB, Jones DP. Bioavailability of dietary glutathione: effect on plasma concentration. Am J Physiol. 1990;259(4 Pt 1):G524-G529.

5. Aw TY, Wierzbicka G, Jones DP. Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact. 1991;80(1):89-97.

6. 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;78(2):293-300.

7. Richie JP Jr, Nichenametla S, Neidig W, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr. 2015;54(2):251-263.

8. Jones DP, Coates RJ, Flagg EW, et al. Glutathione in foods listed in the National Cancer Institute's Health Habits and History Food Frequency Questionnaire. Nutr Cancer. 1992;17(1):57-75.

9. Furukawa T, Meydani SN, Blumberg JB. Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice. Mech Ageing Dev. 1987;38(2):107-117.

10. Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP. Inhibition of influenza infection by glutathione. Free Radic Biol Med. 2003;34(7):928-936.

11. Novi AM. Regression of aflatoxin B1-induced hepatocellular carcinomas by reduced glutathione. Science. 1981;212(4494):541-542.

12. Trickler D, Shklar G, Schwartz J. Inhibition of oral carcinogenesis by glutathione. Nutr Cancer. 1993;20(2):139-144.

13. Schwartz JL, Shklar G. Glutathione inhibits experimental oral carcinogenesis, p53 expression, and angiogenesis. Nutr Cancer. 1996;26(2):229-236.