Glutathione

Neutralizes free radicals

Glutathione (GSH) is a three-amino-acid peptide made of glutamate, cysteine and glycine. It is the most abundant small antioxidant inside cells, at 1–10 mM, about a thousand times more than vitamin C in most tissues. What it uses is the thiol (–SH) group on its cysteine, which readily gives up an electron.¹

It works in a cycle:

1. Glutathione peroxidases (GPx), enzymes that contain selenium, use two GSH molecules to turn hydrogen peroxide into water, or a lipid peroxide into a harmless alcohol. The two GSH become one oxidised molecule, GSSG.
2. Glutathione reductase, which needs FAD from riboflavin, uses NADPH to split GSSG back into two active GSH.
3. The NADPH comes mainly from the pentose phosphate pathway, which needs thiamine, and from niacin-derived enzymes.

GSH also recharges vitamin C, which in turn recharges vitamin E in membranes. The ratio of GSH to GSSG (normally above 100:1 in a healthy cell) is the cell's main measure of oxidative state. When it falls, cells switch on stress responses, and if it falls far enough they die.¹

Supply sets the limit. Of the three amino acids, cysteine is usually in shortest supply, and making glutathione also uses a lot of glycine. In older adults, giving both (GlyNAC) restored glutathione and improved oxidative-stress markers (see Cysteine and Glycine).

Supports detox

The liver handles foreign chemicals in two phases. Phase I (cytochrome P450 enzymes) often makes them more reactive. Phase II attaches something water-soluble so they can be excreted. Glutathione is the main thing attached in phase II. Glutathione S-transferases (GSTs) bind GSH to reactive electrophiles: drug metabolites, carcinogens such as aflatoxin and the benzopyrene in smoke, and the reactive aldehydes from lipid peroxidation. The tagged compound is then exported and broken down into a mercapturic acid that goes out in urine or bile.²

The clearest human example is acetaminophen (Tylenol). At normal doses, a small fraction of acetaminophen is turned into a toxic reactive product, NAPQI, which liver GSH neutralises straight away. In an overdose, NAPQI uses up liver GSH faster than it can be replaced. Once GSH falls below about 30% of normal, NAPQI attacks liver proteins and liver cells die. The antidote, N-acetylcysteine, works by supplying cysteine so the liver can rebuild GSH. Given within 8 hours, it almost completely prevents liver failure (see Cysteine). That's direct evidence that glutathione supply is what limits the liver's ability to detoxify.

The common GSTM1 "null" gene variant, carried by about half of people of European descent, removes one GST enzyme. It's linked to slightly higher risk of some smoking-related cancers, more evidence that this pathway handles real toxins.

Getting more: precursors vs pills

It was long believed that oral glutathione is simply digested back into its amino acids. A 6-month randomised trial partly overturned this. In 54 healthy adults, 1,000 mg/day of oral GSH raised glutathione stores by 30–35% in red cells, plasma and lymphocytes, and by 260% in cheek cells, compared with placebo. 250 mg/day had smaller effects.³ So oral GSH does get in, slowly and at high doses.

The cheaper and better-tested route is still to supply the building blocks: cysteine (from protein, or NAC) and glycine (from collagen, bone broth or a glycine supplement), plus the cofactors that keep it recycling: riboflavin, selenium and enough NADPH from a diet that isn't low in B vitamins.

Top foods

• Protein foods rich in cysteine: beef, salmon, turkey, eggs, cheese
• Glycine sources: bone broth, collagen, skin-on poultry
• Sulfur-rich vegetables: onion, garlic, broccoli. Their compounds (e.g. sulforaphane) switch on Nrf2, which raises the cell's own glutathione production.

Deficiency effects

There's no classic dietary deficiency disease, because the body makes its own glutathione. Low glutathione appears in states of high oxidative stress or low precursor supply: ageing, HIV, poorly controlled diabetes, heavy drinking, acetaminophen overdose and low-protein diets. It shows up as a low GSH:GSSG ratio, raised lipid peroxidation markers and greater vulnerability to toxins and infection.¹ Rare inherited defects in the enzymes that make glutathione cause red cells to break apart and, in severe forms, nerve damage.