Oral Glutathione Supplementation Is Bioavailable After All

Way back in 2007, Art De Vany used to talk about his glutathione supplements and upon looking into it, I heard from numerous sources that it’s simply not bioavailable taken orally. Glutathione is generally regarded as the body’s master anti-oxidant.

Glutathione (GSH) is an important antioxidant in plants, animals, fungi, and some bacteria and archaea, preventing damage to important cellular components caused by reactive oxygen species such as free radicals and peroxides.[2] It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side-chain and the amine group of cysteine (which is attached by normal peptide linkage to a glycine).

It’s not an essential nutrient, since we synthesize it ourselves from the amino acids L-cysteine, L-glutamic acid, and glycine. So, two studies:

jf 2014 01338z 0007

Longtime reader and email correspondent Scott Miller excerpted this from the full text of the first study.

…Witschi et al. (1992) have observed no increase in plasma GSH levels after a single oral supplementation of GSH to healthy human volunteers at 0.15 mmol/kg body weight. The present study confirmed these results [Figure 5(a) and (b)]. Based on these results, it has been suggested that the oral supplementation of GSH does not affect blood GSH levels.

It has been demonstrated that plasma proteins, including albumin, can bind to low molecular weight thiol-compounds through a disulfide bond. Therefore, there is the possibility that supplemented GSH may be transported as a conjugate of protein in the blood, and this has not been examined. In the present study, the effects of the supplementation of GSH on plasma protein-bound GSH levels were examined…

…The present study also demonstrated that only a negligible amount of GSH was bound to plasma protein before the supplementation of GSH. However, the protein-bound GSH significantly (P < 0.01) increased from 60 to 120 min after the oral supplementation of GSH. This is the first report to demonstrate an increase in GSH in the human blood fraction by the oral supplementation of GSH. The protein bound form GSH level in plasma after supplementation of GSH is much higher (>1000 times) than other food-derived peptides such as Val-Tyr 25 and Ile-Pro-Pro 26, but less than the food-derived collagen peptides in human blood.

It has been thought that orally administered GSH is successively degraded to cysteinyl-glycine, cysteine, and glycine by γ-glutamyl-transferase and peptidase. Cysteine could be used for GSH synthesis in cells. Increased levels of protein-bound GSH might be derived from the newly synthesized GSH. The present study also detected fragment peptide (Cys-Gly) and precursor peptide (γGlu-Cys) as protein-bound form in human blood, which suggests some GSH is synthesized from degradation products of GSH.

However, an early study by Kubo (1968) that used 35S-labeled GSH and paper electrophoresis has suggested that GSH could be directly absorbed from the small intestine into rat portal blood. Therefore, there is a possibility that supplemented GSH is directly absorbed into human blood and bound to plasma protein. To solve these problems, further studies on the metabolic fate of supplemented GSH that use 13C-labeled GSH are in progress…

And from the second study.

GSH levels in blood increased after 1, 3 and 6 months versus baseline at both doses. At 6 months, mean GSH levels increased 30-35 % in erythrocytes, plasma and lymphocytes and 260 % in buccal cells in the high-dose group (P < 0.05). GSH levels increased 17 and 29 % in blood and erythrocytes, respectively, in the low-dose group (P < 0.05). In most cases, the increases were dose and time dependent, and levels returned to baseline after a 1-month washout period. A reduction in oxidative stress in both GSH dose groups was indicated by decreases in the oxidized to reduced glutathione ratio in whole blood after 6 months. Natural killer cytotoxicity increased >twofold in the high-dose group versus placebo (P < 0.05) at 3 months.

[easyazon_image add_to_cart=”default” align=”left” asin=”B00BRAZIRM” cloaking=”default” height=”250″ localization=”default” locale=”US” nofollow=”default” new_window=”default” src=”https://ecx.images-amazon.com/images/I/31lQPhNODbL.jpg” tag=”fretheani-20″ width=”144″][easyazon_link asin=”B00BRAZIRM” locale=”US” new_window=”default” nofollow=”default” tag=”fretheani-20″ add_to_cart=”default” cloaking=”default” localization=”default” popups=”default”]Life Extension Glutathione, Cysteine and C, 750 mg.[/easyazon_link] The question is, how much do you need, and is there a potential downside? It’s all very complicated, all intertwined—in my view—with hormesis, autophagy, apoptotic clearance, and the push-pull, yin-yang relationship between methylglyoxal and glutathione. I’m intuitively resistant to the idea that if some is good, more must be better. So many processes seem to have opposing counterparts—inflammation being a classic example. Yes, chronic inflammation is bad, but many forms of acute inflammation are beneficial. Negative feedback mechanisms are enhanced by opposing positive feedbacks, and vice-versa. It’s the way nature operates to balance on the head of a pin.

Those keeping tabs might recognize that much of this kind of thinking was recently introduced in part 1 of a new series: The Hormesis Files: Chronic Ketosis and The Case of The Missing Glutathione. Part 2 is coming soon, probably first part of the new year. But here’s one of the many relevant portions from that first post, which I encourage you to read.

ketogenic Diets, Hormetic Oxidative Stress and Glutathione

What Dr. Eades couldn’t have known, back in 2008, is that the same group of researchers (sans Jarrett) published another exciting paper in 2010—again with rats—showing that a ketogenic diet appears to produce its therapeutic benefits with a hormetic dose of oxidative stress, which activates the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The Nrf2 pathway activates genes that are involved in detoxification of chemicals and antioxidant defense. That kind of stress is a good thing, at the right dose. The Nrf2 pathway itself is described by some as a key hormetic pathway and has been linked to longevity. And in fact, some studies suggest that trying to avoid low levels of oxidative stress is counterproductive.

However, the researchers stumbled onto a potential troubling side effect of ketogenic diets after a few weeks…

…If you didn’t catch that, what this study showed is that chronic ketogenic diets (3 weeks) appear to deplete the liver of glutathione in the same way as taking Tylenol every day!

So, perhaps those most in need of supplementing glutathione, now that we know it’s bioavailable, would be those on low carb and ketogenic diets—as well as those who take Tylenol, or perhaps other analgesics or NSAIDs.

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  1. Duck Dodgers on December 26, 2014 at 18:41

    “…Perhaps those most in need of supplementing glutathione, now that we know it’s bioavailable, would be those on low carb and ketogenic diets…”

    Well, supplementing glutathione could very well be counterproductive to a VLCer if their elevated MG levels are helping to suppress their problematic symptoms.

    As explained in Part I, glutathione reduces MG in the body. Conversely, a ketogenic diets seems to decreas liver glutathione (exporting it out of the liver to the brain and mitochondria), which in turn raises toxic MG in the blood—perhaps to therapeutic levels, for some people.

    Research suggests that the elevated MG levels from a ketogenic diet can suppress epileptic seizures and MG in the blood appears to be an antimicrobial—suppressing viruses and bacterial infections in the brain and other organs.

    So, as an example, if an epileptic takes supplemental glutathione, it might reduce the therapeutic MG coursing through their veins that could be suppressing their seizures. That would be counterproductive. The same thing might be true of someone with a bacterial or viral brain infection.

    What the studies in Part I shows us is that a ketogenic diet is very much like a pharmaceutical—it has measurable side effects, and doesn’t necessarily cure the underlying condition. Taking a supplement to undo the side effects of decreased glutathione might very well undo the very mechanism that may be providing the benefit in the first place.

    It’s all very speculative, of course, since no one even knows for sure why a ketogenic diet may be therapeutic for some conditions.

    • Monte on September 28, 2015 at 16:42

      The systemic availability of oral glutathione (GSH) is negligible; so it must be biosynthesized from its constituent amino acids, cysteine, glycine, and glutamic acid. Some studies done on mice and rats show increased GSH in tissue, blood plasma and organs (liver, kidney, heart, lung, brain, small intestine and skin) after administration of oral glutathione.
      However, there are several interesting observations:
      Mice that were not previously depleted of glutathione showed an increase in plasma glutathione only in lungs.
      Mice that showed significant increase in glutathione concentration were chemically pretreated for 5 days to deplete their glutathione levels. Still, glutathione rose in all organs except in the liver where it is most needed for detoxification.
      The effect of raised glutathione lasted 3 hours on average.
      All mice and rats received glutathione supplementation in doses much higher than the typical 500 mg dosage in human glutathione pills: 100mg/kg of weight for mice. If we do a comparison with human dosages for an average adult weighing 70 kg (approx. 154 lbs.) one 500 mg glutathione pill contains only 7.5 mg of glutathione per kg of weight.
      So, to achieve similar results an adult will have to be severely glutathione deficient and take a minimum of 14 glutathione pills. To maintain the result of raised glutathione an adult will have to take this many pills several times a day.
      Only very small amounts of pre-manufactured glutathione are able to enter bloodstream. Most of it is lost in the digestive tract and cannot effectively raise intracellular glutathione levels in the most important detoxification organs, such as liver, kidneys and lungs, because glutathione is a small protein molecule and gets digested.
      There is a school of thought that contends that glutathione is broken down in the stomach and intestine and effective increases of GSH must come via intravenous administration. However, previous animal studies showed that orally administered glutathione is bioavailable and will enhance tissue GSH levels, Dr. Richie said.
      “Our research showed that in most cases increases were dose and time dependent, and levels returned to baseline after a one-month washout,” he said. “By taking daily GSH supplements, we believe efficacious levels will persist, and that oral intake is an effective means of chronically enhancing the body’s stores.”
      Supplementation with glutathione has been met with little success as the bioavailability of glutathione is low due its transient transport throughout the cellular network. At the current time, the bioavailability of glutathione is thought to be extremely poor due to the hydrolytic enzymes that break down the glutathione upon ingestion.
      Nevertheless, popularity for glutathione administration and supplementation is high due to its primary role to minimize the oxidative stress seen with exercise.

      So is this item really bioavailable in oral formulations??????

  2. Charlene on December 26, 2014 at 20:47

    Is it a valid assumption that taking a supplement should result in higher serum levels of that nutrient to be effective/bioavailable?

    My H has been eating a more nutrient rich diet – cod liver oil, raw milk yogurt, and beef liver – but has not seen a change in 25-OH-D or B12 in his blood work one year later. He’s thus assuming the diet is making no difference to his health. However, his physical symptoms – numbness tingling in extremities, libido, feelings of incontinence – seem stable or perhaps slightly improved.

    He can’t trust his symptoms though without confirmation from lab work and may give up on the diet.

    • SteveRN on December 26, 2014 at 23:59

      In healthcare we call that treating the numbers, not the patient. For example, treating a blood pressure of 85/50, without realizing that is an appropriate blood pressure for an athletic 22 year old with no symptoms of low bp. The labwork is nice, but, if your symptoms disappear, that is what is more important. Having low cholesterol doesn’t mean you will not have a heart attack, and high doesn’t mean you will.

    • Richard Nikoley on December 27, 2014 at 08:25

      That’s just it, Charlene. It doesn’t result in higher serum levels, so it was always held that the oral form didn’t make it past getting destroyed via digestion. It took a new testing method, which found it hiding out, attached to certain proteins.

    • gabkad on December 27, 2014 at 08:36

      Charlene, cod liver oil actually does not contain large amounts of vitamin D3. It does, however, contain much higher levels of vitamin A.

      If you husband has not seen an increase in his B12 levels with liver, then it’s possible he has PA and requires large doses of sublingual methylcobalamin to raise his B12 levels.

      If he has other symptoms of poor digestion then this needs to be evaluated.

    • Will on December 30, 2014 at 20:19

      This is kind of a non sequitur, but you reference Art DeVaney: do you, or any of your readers no why he stopped blogging? His last entry is from late May of this past year (with no hint at the time that that would be his last). Just curious; I always found DeVaney to be an interesting contributor to the world of health and fitness.

  3. Charlene on December 28, 2014 at 10:03

    Thanks everyone!

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