Addressing Glutathione Depletion
Restoration of Glutathione (GSH) level should be approached from four angles:
- Synthesis of new GSH
- Recycling of oxidized GSH
- Protecting current GSH from further depletion
- Finding the cause of GSH depletion
Work on GSH synthesis
- NAC provides Cysteine which is a rate limiting substrate for GSH synthesis.
- Selenomethionine and Sodium Selenite. Selenomethionine was shown to increase Cystine uptake into the cells, so this can be useful as both a provider of Selenium (not efficient though) and an upregulator of Cystine uptake. It seems there is a mysterious “Selenoprotein H” that regulates GSH synthesis. Synthesis of this protein depends on Selenium availability in the body. So selenium appears to be affecting not only GSH recycling (see below), but also GSH synthesis. (R6)
- A second substrate for GSH synthesis is Glutamic acid, which is made in our bodies. However, in some cases it might be beneficial to help the body and supplement with Glutamine.
- Make sure Glycine level in blood is not low, because Glycine is a third substrate required for GSH synthesis.
- Magnesium appears to be a cofactor for the both steps of synthesis by GCL and GS enzymes. (R2, R3)
- Sulforaphane/MSM (R1)/Resveratrol can help to force-start GSH synthesis.
- Zinc (optional if not deficient). Zinc deficiency reduces expression of GCL enzyme, which makes Gamma-glutamylcysteine. (R4)
Molybdenum for Cysteine metabolism
When taking increased amounts of Cysteine (NAC), you may need extra Molybdenum to support the enzyme Sulfite Oxidase that converts Sulfite to Sulfate. Otherwise, you may get symptoms of “Sulfur intolerance”. However MoCo synthesis consumes SAMe, so taking too much of molybdenum supplement may decrease amount of SAMe in the brain, and can cause insomnia (personal experience).
Notes from personal experience
Taking Sulforaphane or MSM without the source of extra Cysteine, or when Glycine is low resulted in increased irritability (observed in one adult and three kids from different families).
The hypothesis is that forcing GSH synthesis in the context of low Cysteine/Glycine will deplete the pools even more, which is counterproductive.
Supplements
- NAC (N-Acetyl-Cysteine)
- Magnesium
- Selenomethionine, Sodium Selenite
- Sulforaphane
- MSM (Methylsulfonylmethane)
- Resveratrol
- Glycine (optional)
- Glutamine (optional)
- Molybdenum (optional)
- Zinc (optional)
Work on glutathione (GSH) recycling
- Recycling requires FAD – an active form of vitamin B2 in the cells - which means you need to have sufficient levels of Riboflavin (B2), Zinc, Copper. Also Iodine and Selenium (to make active thyroid hormone T3 which regulates metabolism).
- you need Cysteine to be able to make enough Glutathione Reductase – an enzyme that does actual recycling.
- you need sufficient amount of NADPH in the cells, larger part of which is created in the Pentose Phoshate Pathway. That pathway requires B1, B3 and Magnesium.
Supplements
- Thiamine (vitamin B1)
- Riboflavin (vitamin B2)
- Selenium. Inorganic forms deplete GSH, but are more efficient at getting to work. Organic forms don’t deplete GSH, but need transsulfuration pathway working efficiently and are generally much slower in providing selenium)
- Niacin (vitamin B3)
- NAC (N-Acetyl-Cysteine)
Supplements that you may need to support activation of B2:
- Iodine
- Magnesium
- Zinc
- Copper. Be careful, copper depletes GSH and is not recommended without assessing its level first.
- Cysteine (NAC)
Search for causes of GSH depletion
Toxic substances deplete Glutathione (e.g. metals, some metabolites produced in the body). But also useful minerals can use up GSH temporarily: copper uses GSH for intracellular trafficking, Vitamin B12 adoption requires GSH too. So when you’re addressing high oxidative stress, be aware that some supplements, while being useful, can deplete GSH.
Lab tests that reveal toxic metals, infections and metabolic abnormalities can be very helpful.
A typical cause of high oxidative stress can be vitamin or mineral deficiencies that derail metabolism and shifting it to alternative pathway or even straight ROS production like in cases of B1 deficiency or Iron deficiency.
(TODO: add references to ROS production by AKGDH when B1 is low; ACO2 when Iron is low; NOS uncoupling).
Role of Ascorbic Acid (Vitamin C)
Ascorbic Acid (AA) can be used to protect GSH from oxidation, but high intake of ascorbic acid will also decrease availability of GSH temporarily, because GSH reduces (restores) AA from oxidized form (dihydroascorbic acid):
Ascorbate spares glutathione indicating that these compounds have similar antioxidant actions. Ascorbate may have reductive functions that are not efficiently performed by glutathione. Although glutathione normally functions to maintain ascorbate, alpha-tocopherol, and other cellular components in reduced states, ascorbate can serve as an essential antioxidant in the presence of severe glutathione deficiency. (R5)
From personal experience: it makes sense to take small doses of Ascrorbic Acid frequently during the day, to avoid acute GSH depletion.