Glutathione & Detoxification: The Methylation Connection

In my previous article, I expelled many of the myths surrounding detoxification, while simultaneously highlighting the importance of cellular antioxidants with respect to detoxification processes. One such important cellular antioxidant is Glutathione, commonly abbreviated as GSH.

Understanding The Role Of Glutathione In Cell Health & Detoxification

Glutathione is one of the most important cellular antioxidants in your body. It is made up of 3 amino acids: glutamine (the most abundant amino acid in your body), glycine (the simplest amino acid), and cysteine (a sulfur-bearing amino acid). Glutathione acts as a powerful antioxidant, preventing the formation of free radicals and reactive oxygen species (ROS), which are the major threats to cellular and organ toxicity.

Glutathione is sometimes referred to as a redox molecule. Redox is a process whereby a molecule undergoes cycles of both "reduction" and "oxidation". When a molecule undergoes oxidation, it loses electrons, and its oxidation state is increased. When a molecule undergoes reduction, it gains electrons, and thus there is a decrease in the oxidation state. Think of it this way: when glutathione gets used up, it is oxidized; it loses electrons. That oxidized (used up) glutathione can be re-converted into a usable form (reduced form) through reduction processes.

The key point to remember is that if there is a higher amount of oxidation to glutathione, and a lower amount of its reduced form, this is a major marker of increased cellular toxicity, and free radical activity.

Glutathione Protects Your Organs

All organs of the body contain cellular antioxidants, in order to protect you from free radicals and toxicity. This is especially true of the "high energy demand organs" such as the liver, heart, lungs, kidneys, gut and brain. These organs use up an enormous amount of ATP (biological energy) in order to continuously function. Think about it: does your brain or liver ever stop working? No. And if these organs are constantly at work, they are using up ATP (biological energy). Any time there is ATP used up by mitochondrion, free radicals are produced as a normal end-product. These free radicals must be kept in check, otherwise organ function is compromised and toxicity ensues.

Additionally, due to the ubiquitous presence of environmental toxins in the body, our cells and organs have to synthesize and use up glutathione (and other cellular antioxidants) in order to prevent these toxins from damaging our cell's functions.

Glutathione is critical for the detoxification of carcinogens such as benzene (commonly found in automotive exhaust), heavy metals such as mercury, cadmium and lead, and common chemicals such as BPA. Remember also, that if there is an increased exposure to environmental chemicals, the demand for glutathione synthesis increases. The higher the demand for glutathione production, the more glutathione gets used up.

If our reduction processes can't reconvert the "used up" (oxidized) form of glutathione, our toxic burden increases. So we MUST work to decrease our body burden of toxins, as well as supply the raw material nutrients through an optimal diet.

Glutathione, Genetics & Methylation

A lot of attention has been placed on glutathione and methylation. This is because the methylation cycle is directly joined with the transsulfuration pathway. Transsulfuration is how we make glutathione.

In short, some of the homocysteine that is made from methylation reactions is used to make cysteine, which then combines to form glutathione.

If we have certain, expressive methylation gene mutations that are limiting our ability for normal enzymatic reactions, our glutathione synthesis and utilization may be directly compromised. CBS (cystathionine beta synthase) is one such gene/enzyme. MTHFR, MTRR, AHCY are others.

With or without these gene mutations, if we lack the nutrient cofactors for glutathione synthesis or methylation reactions, we may not be producing enough glutathione.

Because of its importance, lets look at the cofactors for the CBS enzyme (which is the gateway enzyme in glutathione production). The following nutrients are known cofactors in CBS activity:

  • P5P (the active form of Vitamin B-6)
  • Serine
  • Heme

Vitamin B-6 deficiency may be more common that you realize. Certain populations may be at an increase risk of B-6 deficiency. This may be especially true of women using contraceptives, the elderly, those with pyroluria, and those who consume alcohol on a regular basis. The research suggests that these populations are at a high risk of B-6 deficiency.

It is significant to address that any serious glutathione promotion therapy, should involve P5P or Vitamin B-6.

How Do I Know If I Have Low Glutathione?

Probably the best measure of glutathione activity is plasma glutathione, both in its reduced and oxidized states. Some research has suggested that RBC (red blood cell) glutathione may be very good as well. The problem I see with RBC glutathione is that the red blood cells are huge carriers and exporters of glutathione, and therefore what is in a red blood cell may not represent what is in other cells or tissues (4).

A high plasma oxidized GSH and low reduced GSH indicate a higher oxidative stress burden, and a need to pay closer attention to methylation functions.

Other methods of monitoring the activity of glutathione include urinary organic acids testing, specifically pyroglutamatic acid. Low levels of this metabolite suggest poor recovery of glutathione.

While not definitive, a low serum albumin (<4.1 or <41 in SI units) could indicate glutathione depletion. This is because thiol-containing molecules such as glutathione are major constituents of the albumin.

How Can I Raise My Glutathione?

We must give attention to the fact that no two people are alike, and that one size fits all nutritional approaches fail to work. This is true of glutathione therapies. Genetic factors, pre-existing toxicities, dietary intolerances all must be considered with each person.

Much has been discussed in the public sphere regarding GSH therapies. Liposomal forms of glutathione are probably considered the best to use orally, as these will be designed to bypass gastric acid, so that GSH can be taken up directly by intestinal cells.

I am more a fan of using nutrient precursors to raise glutathione endogenously, rather than giving the "already made product" (liposomal GSH or reduced GSH). In this way, you help the body to make its own, by giving the important cofactors. Some of the important glutathione cofactors and nutrient synergists include:

  • NAC
  • P5P
  • Glutamine
  • Glycine
  • Selenium
  • Vitamin C
  • Vitamin B-12

Much has been written about the upregulation and downregulation of the glutathione pathways, namely the controversial activities of the CBS gene/enzyme. Whatever the case may be, you must realize that everything comes down to the needs of the individual.

In our nutritional consulting practice, we carefully select and recommend the right nutrients at the right time, for each client in question. We may recommend the evaluation of certain tests, in order to determine the best route for glutathione therapy and enhanced detoxification procedures. Please feel free to contact us below to learn more about our nutritional consulting services and programs.

If you are interested in our methylation MTHFR educational presentations, please go here.