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GlutathioneBy Joel Brind, Ph.D.

The subject of glutathione (GSH) came up in my last post on diet and inflammation, some of the comments reflecting the popularity of GSH as some sort of miracle molecule among alternative health purveyors and practitioners. Among the commenters, Sarah said: “Is this total BS? Is glutathione really the miracle substance some alternative med doctors say that it is?”

The short answer to the second question is yes: I would agree that GSH can be called–as one popular alternative physician (Mark Hyman) puts it—”the mother of all antioxidants.” After all, GSH is a universal and tremendously versatile intracellular antioxidant and detoxifier of other reactive chemical stressors (like formaldehyde and acetaminophen). GSH is, in fact, both reusable and indispensable. It is made in the liver, although in highest concentration in red blood cells (where oxidative stress is naturally highest), but important in the liver itself, as well as other organs, including the brain.

But I also have to say that there is a lot of BS out there about GSH, because of the type of simplistic thinking that is all too common among scientists and health gurus these days. So the simplistic story typically goes something like this:

  1. GSH is a good thing, the body’s most important endogenous (non-essential, made by the body itself) antioxidant/detoxification molecule.
  2. Studies show that GSH is highest in the young and the healthy, and lowest in the old and the sick. Therefore, raising blood levels of GSH is a good thing.
  3. We can raise blood levels of GSH by directly adding GSH (although this is often not practical, as it does not survive the digestive system well).
  4. We can raise blood levels of GSH by adding the limiting precursor—the amino acid cysteine—to the diet as a supplement.
  5. Therefore, we can improve health status by cysteine supplementation.

Now, let’s actually think this through:

  1. GSH is a good thing, the body’s most important endogenous antioxidant/detoxification molecule.
  2. The liver makes more GSH in response to oxidative/toxic chemical stress.
  3. Substances which raise blood levels of GSH—even a precursor like cysteine—may do so because they increase (or reflect an increase in) oxidative/toxic chemical stress, the body making more GSH to neutralize the increased stress.
  4. Therefore, we might actually make things worse with cysteine supplementation.

So it’s possible that adding a supplement that increases GSH might do more harm than good, if we fail to consider the body’s exquisite natural system of checks and balances.

Let’s consider an analogous situation: Red blood cells are the indispensable oxygen carriers in the blood. If you don’t have enough of them, you have anemia. The body will compensate and make more of them if you deprive it of oxygen. You can do this by, say, moving from New York (close to sea level) to Denver (a mile high), where the oxygen content of the air is lower, and it works. You can also do it by smoking cigarettes, subjecting your body to chronic carbon monoxide poisoning. Ergo, smoking cigarettes can cure anemia!

Getting back to GSH, let’s go back to the metabolic diagram—Figure b from my last post (reprinted below) on diet and inflammation—which shows how the liver handles (i.e., gets rid of) excess methionine coming in from a typical high protein (e.g., muscle meat) meal:

Joel Brind glycine 2In this diagram (active pathways shown by green arrows), methionine comes in at the lower left. As shown by the first star-pointed yellow arrow, the presence of methionine literally turns on the activity of the enzyme (called MAT) which turns methionine into SAMe (a necessary activation step, either to use the methionine as an important methylator or to get rid of it). SAMe is a very reactive (and therefore, potentially toxic) compound, and the liver gets rid of it by harmlessly giving the methyl group to a molecule of glycine (a step called transmethylation, performed by the enzyme GNMT).

That takes care of the “meth” part of methionine, so now the liver has to deal with the “thionine” part, by a process called transulfuration. When methionine gives up its methyl group, it becomes the amino acid homocysteine (Hcy; see lower right of figure). Hcy can be remethylated to methionine, but that process is turned off when methionine (and therefore, SAMe) is abundant (see black dashed arrow from right to left near bottom of figure).

That’s where GSH synthesis comes in. As indicated by the long yellow star-pointed arrow, the presence of increased SAMe literally turns on the enzyme CBS, which combines the amino acids Hcy and serine, to form cystathionine. This is the key committed step in the synthesis of cysteine. In turn the availability of cysteine determines how much GSH is made. Add more cysteine, and you get more GSH, assuming there is enough glycine around, of course: If glycine is inadequate, you can’t make more GSH, because each molecule of GSH has the same amount of glycine as cysteine (and the same amount as gelatin, for that matter). Meanwhile, adding more cysteine makes things worse, by decreasing the amount of methionine needed to make cysteine for making proteins, thus exacerbating the excess of methionine.

So the bottom line is that the liver makes more GSH as a response to excess levels of methionine and its unstable derivative, SAMe, so that toxic downstream products of SAMe can be detoxified. If glycine is deficient, adding more cysteine won’t help.

Note also that, when we consider the entire process of detoxifying a single molecule of excess methionine, one molecule of glycine is used up in transmethylation (by GNMT), a molecule of serine (which is made in one step from glycine) and another molecule of glycine is used up in making one molecule of GSH. Thus, 3 glycine equivalents are used in order to dispose of one excess molecule of methionine. Although glycine is nonessential, the liver can not keep up if the diet is methionine-loaded (with muscle meats) and glycine-deficient (with the glycine-rich bones and connective tissues discarded).

So much for theory, and experiments in laboratory animals. After all, the information presented here is mainly derived from experiments in rats. Human studies must provide the proof of the pudding.

Accordingly, a landmark 2010 study by Gall et al., looking at 485 different metabolites in the plasma of 399 non-diabetic Americans, found the following: In the 138 subjects with insulin resistance (a prediabetic state, compared to the 261 subjects with normal glucose tolerance), the single most reduced substance was (drum roll, please) glycine! (Serine was also significantly reduced.) Meanwhile, 3 of the top 10 metabolites with increased concentrations in the insulin resistant subjects were alpha hydroxybutyrate (a direct product of alpha ketobutyrate), alpha ketobutyrate and cysteine. In other words (looking back at the figure), there was a back-up of biochemical metabolites on the pathway for making GSH, fitting in perfectly with the observed deficiencies in glycine and serine.

In terms of a placebo-controlled clinical trial, a 2008 study by Cruz et al. of 74 Type 2 diabetic patients in greater Mexico City tested a 3-month course of glycine supplementation (15 grams/day). Patients who received the glycine showed significant reductions in blood inflammatory markers, and enjoyed reductions of fasting glucose from 183 to 140 and of Hemoglobin A1C (the standard marker for long-term blood glucose control) from 8.3 to 6.9, right down to the threshold values for diabetes.

Data like these, which so clearly confirm the theory, put glutathione and its precursors in proper perspective, and helped drive me to formulate and sell the glycine supplement Sweetamine. And btw, feeding rats supplemental glycine makes them live longer, even as it reduces the GSH in their livers by more than fourfold. So the answer is no: More GSH is not necessarily better.

About the Author

Joel BrindJoel Brind, Ph.D. has been a Professor of Biology and Endocrinology at Baruch College of the City University of New York for 28 years and a medical research biochemist since 1981. Long specializing in steroid biosynthesis and metabolism and endocrine-related cancers, he has specialized in amino acid metabolism in recent years, particularly in relation to glycine and one-carbon metabolism. In 2010 he founded Natural Food Science, LLC to make and market glycine supplement products via http://sweetamine.com , which includes his own blog HERE.