Supporting Glutathione Levels and Function – The Many Facets
** A work in progress, check back for updates! **
The maintenance of glutathione redox homeostasis and having a sufficient pool of glutathione to readily combat the daily stresses and toxins we face is a complex system with many factors effects the levels and function of glutathione.
1 – Cysteine supply and intra-cellular availability
Glutathione is comprised of three amino acids, glutamine, glycine and cysteine. The special properties of glutathione come from the Sulphur atom contained in the cysteine.
It is this cysteine which is the rate limiting component in the synthesis of glutathione, so glutathione supplementation has focused on providing cysteine. The reactive nature of it means it is a challenge to provide cysteine inside this cell before it has reacted in the digestive system or blood stream and become inactive form cystine, which is two cysteine’s bonded together by their sulfur atoms. (Note the subtle different in spelling, cysteine and cystine!)
Another consideration is where someone is in a state of immunoexcitotoxicity, which can happen from causes such as autism and chronic head trauma.
“The cystine/glutamate X c antiporter is an exchange system where intracellular glutamate is exchanged for extracellular cystine, so as to supply cysteine for glutathione (GSH) generation.  Excess extracellular glutamate prevents exchange and lowers astrocytic GSH. The astrocyte is the major source of neuronal GSH. Under such conditions, the neuron becomes highly vulnerable to conditions of oxidative stress, as seen with concussive brain injuries and immunoexcitotoxicity.”
N-Acetyl-Cysteine has been the most commonly used supplement for raising glutathione levels, however it has low bio-availability. Researchers have spent decades developing new cysteine and glutathione compounds (Prodrugs) which can deliver either cysteine or glutathione into the cell. There is one commercially available glutathione prodrug, S-Acetyl-GSH, and the most bio-available cysteine compound available on the market is RiboCeine.
2 – Activation of Nrf2
Before I say too much on Nrf2 I highly recommend watching this YouTube on DNA Transcription first which helped me understand clearly some of the terms I had been reading in the medical journal articles.
While glutathione is known as the master anti-oxidant, Nrf2 is the master regulator of the anti-oxidant response.
Reactive Oxygen Species and toxins (heavy metals etc) cause the Nrf2 protein to separate from the Keap1 protein, which is normally bound to. Then it move to the nucleus of the cell where it binds with the ARE (Antioxidant Response Element) which encodes various anti-oxidant, detoxifying, and DNA repair enzymes.
Most relevantly the enzymes include all the glutathione enzymes which are required for synthesis, anti-oxidant function, detoxification function, and recycling of used glutathione.
Rather than repeat what’s already been well written on Nrf2 for more details read this article Nrf2, a Guardian of Healthspan and Gatekeeper of Species Longevity
Many of the ‘anti-oxidant’ properties of plant extracts, are in fact due to the activation of Nrf2 rather than acting as a direct anti-oxidant. Some of the most well studies ones include sulforaphane (from cruciferous vegetables, and is in the most highest concentration in broccoli sprouts) and curcumin, the yellow pigment in the spice turmeric.
Human clinicals have shown that these plant Nrf2 activators can increase glutathione levels. However many of these Nrf2 products (such as ProVantage and Nuley) do not contain any cysteine compounds. My concern here is that these Nrf2 activators may also deplete glutathione in the long run as some are in fact conjugated by glutathione, so ideally Nrf2 activators should be combined with a cystine/glutathione compound (such as with Cellgevity).
It is concluded that SFN [sulforaphane] undergoes metabolism by S-oxide reduction and dehydrogenation and that GSH conjugation is the major pathway by which the parent compound and its phase I metabolites are eliminated in the rat.
Also GSH Depletion Greatly Diminishes the Nrf2 Expression of Antioxidant Genes. So the lower levels of glutathione means lower levels of the ezymes which create glutathione and are required for a its function. Potentially a vicious cycle, hence the importance of always taking a two-pronged approach of both supplementing with cysteine pro-drugs such as RiboCeine and plant-based Nrf2 activators.
(source: Genetic dissection of the Nrf2-dependent redox signaling-regulated transcriptional programs of cell proliferation and cytoprotection)
3 – Genetics
As discussed glutathione’s critical roles can require the presence of either the enzyme GPx (glutathione peroxidase) or GST (glutathione s-transferase). These are not just a single enzymes, but a family of enzymes with slightly different roles and have different concentrations in different tissues/organs.
Glutathione Peroxoidase is required for anti-oxidant function glutathione, and glutathione s-trasferases are required for it detoxification function.
There are eight genes for GPx which are GPX1 through to GPX8. There are 9 classes of GST enzymes, which some classes have multiple members.
We all have slightly different genetics, and there exists common genetic variations (alleles) which can cause some of these GPx or GST enzymes not to be expressed properly.
About 50% of the population have a null allele of GSTM1 which means it is non-functional.
A small examples of journal articles investigating the links of these polymorphisms are:
Can anything be done to assist those with a null GSTM1? A number of research articles have look at sulforaphane and GSTM1 alleles, particularly in regards to prostate cancer.
Unfortunately the results have been that people with a null GSTM1 have less benefit from sulforaphane consumption, those this may highlight the need for those with these poorer genetics to consume even higher levels of Nrf2 activating phytochemicals.
4 – Epigenetics
Epigenetics is the changes in gene function which occur other than by changes in the underlying DNA. Two key ways gene expressions is modified is through methylation and histones. For as essential, brief overview of epigenetic modifications watch this entertaining YouTube video first on Epigenetics by the SciShow.
Methylation is where methyl groups attach to the DNA and effectively turn off that gene. Histones wrap around the DNA and modify how much a gene is expressed.
Where this is relevant for glutathione production is the action Nrf2 can be inhibited by these epigenetic changes from poor diet, stress etc.
For example there is a number of research papers showing that the expression of Nrf2 can be inhibited by epigenetic modifications, and that these changes can be reversed with the Nrf2 activators Sulforaphane and Curcumin (both ingredients in the glutathione formulation Cellgevity)
Interestingly one way some cancer cells have increased cytoprotection is through epigenetic modifications. Normally Nrf2 is bound with the KEAP protein in the cystol . It was found in cancerous human colorectal cells that the KEAP region was hypermethylated, reducing its mRNA expression, which in turn increased nuclear Nrf2 and downstream ARE (Antioxidant Response Element) gene expression.