11. GSH Facts and Fallacies

There is substantial confusion in the commercial literature about the absorption of GSH from the diet, and about the way the body makes and distributes GSH. A broad review of the science on the subject can give us a more complete picture.

• Many foods contain some GSH, especially fruits, vegetables, and meat.

• GSH is readily absorbed from food or supplements. The absorption is essentially passive. Cells lining the intestines absorb dietary GSH temporarily, then pass it on into circulation.⁴¹

• 80% of GSH in circulation is broken down by the kidneys into separate amino acids.⁴²

• Most cells cannot efficiently absorb GSH from circulation. The few that can use circulating GSH include the cells lining the digestive, respiratory, and urinary tracts (epithelial tissues), and some blood cells. These are the only tissues likely to get pre-formed GSH from the diet.⁴³

• Plasma (blood fluid) levels of GSH are normally quite low. In trauma or acute infection, plasma levels increase as the liver releases more GSH into circulation, but the kidney continues to rapidly metabolize serum GSH.⁴⁴

• Highly oxidative tissues such as the liver, kidney, and heart contain the highest concentrations of GSH.⁴⁵ Heavy demand for GSH is also found in the cells of the muscles, nerves, lungs, and immune system.

• For the vast majority of tissues, GSH is not supplied by the diet, made in the liver, or delivered by the blood; it is made inside the cells. In mammals, after weaning, the cells produce GSH through two main pathways:

1. The enzymes GGC (gamma-glutamylcysteine) synthetase and GSH synthetase assemble GSH from amino acids.
2. Glutathione reductase reduces oxidized GSH (called GSSG, or glutathione disulfide) to recreate active GSH.⁴⁶

• A few so-called "prodrugs" can temporarily increase GSH levels in the cells. For instance, NAC (N-acetylycysteine) is used in emergency medicine to treat acetaminophen poisoning. It works by raising liver GSH, which substantially increases liver detoxification capacity. All of these drugs cause moderate to severe side-effects due to their tendency to increase oxidation even while they raise GSH levels.⁴⁷

• Supplements of l-cysteine have little effect on GSH levels. Mild to moderate side-effects at physiologically active dosages are generated by the spontaneous auto-oxidation of this unstable free amino acid.⁴⁸

• The production of GSH in the cells, from amino acids, is rate-limited by "negative inhibition feedback." As cellular GSH levels increase, the production of the enzyme GGC synthetase slows down, which reduces creation of GGC. Without GGC, GSH cannot be produced. This typically places an upper limit on cellular GSH values.

• Providing pre-formed GGC, as found in mother's milk, offers the cells a way to produce GSH without the rate-limitng step. This gives the cells the potential to achieve higher cellular GSH levels than would otherwise be possible.⁴⁹

• A variety of whey protein products are available for human and animal nutrition. They include whey protein concentrates, whey protein isolates, and ion-exchange whey proteins. Though such products may contain some undenatured whey proteins, they are made with pasteurization and handling procedures that destroy the natural forms of the more fragile milk proteins and dipeptides, including the vital GGC. Extensive testing of a broad range of whey products has shown that none of them provide the unique benefits of patented milk serum isolate.^{50,51,52,53,54}