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. 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:
- Increase in the Protein-Bound Form of Glutathione in Human Blood after the Oral Administration of Glutathione
- Randomized controlled trial of oral glutathione supplementation on body stores of glutathione
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.
Life Extension Glutathione, Cysteine and C, 750 mg. 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.