Research-proven nanosphere-encapsulated glutathione delivery system can help …

Slaughter Free Radicals
Glutathione participates directly in the neutralization of free radicals and reactive
oxygen species that are generated within cells and at sites of inflammation

Richard Kaufman, PhD

T

he tripeptide glutathione is not an essential nutrient, meaning it does not have to be obtained via food. That’s because it can be synthesized in the body from the amino acids L-cysteine, L-glutamic acid, and glycine. But try to live without an abundance of glutathione, and you are at the mercy of the four horsemen of apocalyptic destruction: superoxide radicals (O2-), hydroxyl radicals (OH-), peroxyl radicals (RO2-), and alkoxyl radicals (RO-), not to mention other Orc-like savages that assid­uously assault us though oxidative damage. Indeed, glutathione (aka GSH) is our primary endogenous (made in the body) defense against these deadly hordes.

The sulfhydryl (SH) thiol group of cysteine serves as a proton donor and is responsible for the biological activity of glutathione (thus GSH). Cysteine is the rate-limiting factor in cellular glutathione synthesis, but this amino acid is relatively rare in foodstuffs. Unfortunately, glutathione is not very bioavailable. However, in a reduced state, it can be more efficiently presented for uptake via a stabilized and protective phospholipid nanosphere intraoral delivery system. When so delivered, glutathione can be efficacious, and utilized as the main intracellular defense against oxidative stress, regulating the cellular redox potential, and maintaining the immune system. Whether glutathione is manufactured inside or outside the body, glutathione is critical for the well being of cells.

Glutathione is the Most Powerful Antioxidant Produced by Cells

Glutathione is found in all cells in the body, in the epithelial lining fluid of the lungs, and—at much smaller concentrations—in the blood. GSH is the smallest intracellular nonprotein thiol (molecule containing an SH or sulfhydryl group) molecule in the cells. This characteristic allows for its potent antioxidant action and enzyme co­factor properties, and supports a multifaceted thiol exchange system, which regulates cell activity.

Glutathione participates directly in the neutralization of free radicals and reactive oxygen species that are generated within cells and at sites of inflammation. This antioxidant horde-buster also plays a major role in the detoxification of toxic xenobiotics and carcinogens, facilitating cellular immune functions, providing neuro­protection, and helping to maintain exogenous antioxidants such as vitamins C and E in their active reduced forms. Glutathione also protects the tissues of the arteries, brain, heart, kidneys, the lens of the eyes, liver, lungs, and skin from free radicals. In fact, glutathione is considered the most important antioxidant because it is the only antioxidant capable of working with enzymes. One enzyme, glutathione peroxidase, works with glutathione to prevent membranes from being oxidized.

The highest concentration of glutathione is found in the liver, making it critically important in the detoxification and elimination of free radicals. Accumulation of these dangerous compounds can result in oxidative stress, which occurs when the generation of free radicals in the body exceeds the body’s ability to neutralize and eliminate them. Free radicals are highly reactive compounds created in the body during normal metabolic functions; they can also enter the body through the environment.

Indispensable and Multi-Functional

Metabolically, glutathione has many functions. For example, glutathione plays a substantial role in the functioning of the body’s immune system. Its antioxidant property makes it vital to white blood cells (lymphocytes), as it allows them to reach their full potential during oxygen-requiring activity of the body’s immune response.

Similar to the liver, white blood cells in their immune response also aid in detoxification of the body—and as glutathione levels decrease, so does the body’s ability to eliminate dangerous toxins. This leads to the death of white blood cells—thereby weakening the body’s immune system. Glutathione binds to toxins, forming a water-soluble complex, which is ultimately excreted in the urine or bile as waste. Other antioxidants in the body depend on glutathione as well. Glutathione recycles vitamins C and E after they have been oxidized—therefore playing a decisive role in their normal function.

Oxidative Stressors that Can Deplete Glutathione:

  • Ultraviolet and Other Radiation
  • Household Chemicals
  • Acetaminophen Poisoning
  • Cigarette Smoke
  • Exhaust From Motor Vehicles
  • Heavy Metals
  • Other Environmental Toxins
  • Viral Infections
  • Surgery
  • Inflammation
  • Burns
  • Septic Shock
  • Dietary Deficiencies of GSH Precursors
  • Enzyme Cofactors

Glutathione is essential for the synthesis of DNA precursors and immune functions. Lymphocytes function, T-cell proliferation, interleukin-2, cytotoxicity and NK cell activity depend upon glutathione. Over 80,000 scientific articles have described the impact of glutathione. Alcoholics have low glutathione. So do people with Alzheimer’s disease, diabetes, celiac disease, liver disease, lung disorders, asthma neurodegenerative diseases, Chronic Fatigue Syndrome, and inflammatory bowel disorders. In fact, most people with an infectious and inflammatory disorder have a low level of glutathione for crucial protection.

Children with autism are predisposed to low glutathione, so they can’t detoxify normally. Glutathione is suggested as a promising treatment to combat the oxidative stress found in HIV-infected people. Long-lived women have high levels of glutathione, and people with Parkinson’s disease benefit from treatment with glutathione. And this is just the beginning.

Protection Against the Consequences of Radiation Exposure

Currently, there is growing concern about our exposure to ionizing radiation. Much of the actual damage from radiation is due to runaway oxidative stress from radiation exposure and consequent DNA damage. Radiation causes a depression of our natural antioxidant protection systems, especially the glutathione system and superoxide dismutase. Taking glutathione may enable the activation master switch called “Nrf2 antioxidant response element pathway.” This master switch signals genes to create intracellular antioxidant (GSH and MnSOD) detoxification proteins and enzymes in an unfired manner. This provides both radiation protection and detoxification.

As one researcher put it, “Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including seizure, Alzheimer’s disease, Parkinson’s disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.”

Past studies using intravenous or intramuscular glutathione found it to be valuable in the following uses:

  • Addressing Parkinson’s disease
  • Preventing surgical clot formation
  • Reducing the side effects and increasing the efficacy of chemotherapy drugs
  • Reducing blood pressure in people with diabetes who had high blood pressure.
  • Increasing sperm counts in men with low sperm counts.

Since numerous diseases, wasting and infectious states are associated with a deficiency of glutathione, there is growing interest in its therapeutic use. But despite the wide acclaim for glutathione’s properties, glutathione has negligible systemic bioavailability when taken orally. Ingested glutathione is extensively metabolized in the gut before reaching the bloodstream. The human intestinal tract contains significant amounts of the enzyme gamma-glutamyltranspeptidase that breaks down glutathione.

A Nanosphere by Any Other Name . . .

Nanotechnology is hot these days, and with good reason: although still in its infancy, it represents an enormous leap toward a future of scientific and technological marvels that will make today’s high-tech world look quaintly primitive to generations yet unborn. Of course, much of what passes for “nanotechnology” today is just hype (sexy terms sell) or wild speculation—that’s inevitable.

Human nanotechnology
Most real-world applications of nanotechnology still lie far in the future, because they will require extremely sophisticated fabrication techniques that are still being developed (or have yet to be imagined) by scientists and engineers. A few simple nanotech-based products, however, have entered the market, primarily in the textile, cosmetics, food, and pharmaceutical industries. Most are based on nanospheres (or nanoparticles—not all nano-objects are spherical), which are easy to make.

What’s not easy, however, is to tailor the nanospheres’ physical and chemical properties, such as size distribution, crystal structure (in the case of solid particles), surface electric charge, chemical reactivity, long-term stability, etc. Controlling these properties precisely is difficult but vital, because the nanospheres’ behavior under any set of conditions, such as those of the human digestive tract and beyond, will depend critically on them. Being able to tailor-make nanospheres for particular purposes in this way is one thing that distinguishes modern nanotechnology from the nanotechnology of the past.

Thomas Graham
(1805–1869)
Say what? Nanotechnology has a past? It certainly does, going back at least to the ninth century, when Mesopotamian artisans developed chemical techniques that produced nanoparticles in ceramic glazes, yielding a glittering metallic sheen called luster. But nanotechnology (under a different name) didn’t become a scientific discipline until 1861, when the Scottish physical chemist Thomas Graham founded the field of colloid science, which is based almost entirely on the physical and chemical properties of particles in the (guess what?) nano­meter range.*


*The term nanotechnology was first used and defined in 1974, by the distinguished Japanese engineer Norio Taniguchi.


Colloidal dispersions, or colloids, exist when clusters of gas, liquid, or solid particles in the nanometer size range are dispersed in other gases, liquids, or solids in which they’re not soluble. All but one of the nine possible types of colloid combinations are known (the exception being gas in gas, because all gases are totally miscible). The eight types are called foams (gas in liquid), solid foams (gas in solid), liquid aerosols (liquid in gas), emulsions (liquid in liquid), gels (liquid in solid), solid aerosols (solid in gas), sols (solid in liquid), and solid sols (solid in solid).

The literature on colloid science is enormous, because it’s a diverse and fascinating subject and because colloids are common in nature. Our bodies, e.g., are chock full of colloids: bodily fluids, including the cytoplasm of every cell, are not just solutions of soluble molecules but also colloidal dispersions of insoluble molecules, and of soluble molecules so large that they’re in the colloidal (nanometer) range. Much of physiology could be thought of as applied colloid chemistry.

Colloid science and nanotechnology are interesting not because the laws of physics and chemistry are different in the nano­domain—they’re not—but because the ways in which those laws are manifested there lead to unusual material properties and pose special challenges for mathematical analysis and interpretation. Nano-objects exist in a kind of no-man’s-land between bulk matter, where quantum mechanics is largely irrelevant, and atomic and molecular matter, where it’s utterly dominant. The fact that nanoscale objects, unlike bulk matter, have an enormous surface area in proportion to their volume is extremely important in their physics and chemistry.

Bovine nanotechnology
The main difference between colloid science and nanotechnology—and the line is blurry—is that in the latter, the particles are produced in more or less precise ways to have specific, desired characteristics under specific sets of circumstances, so as to exploit not only the unique physical properties associated with that size domain but also the chemical properties that are “engineered in.”

By the way, drug- or nutrient-delivery vehicles containing solid lipid nanospheres are sols. Other examples of sols are milk, paint, pigmented ink, and all your bodily fluids.

The Failure of Orally Administered Glutathione

Although orally administered glutathione is efficiently absorbed in mice and rats, the same may not be true for glutathione supplements in man. For example, a single oral dose of 3000 mg of glutathione did not significantly raise blood glutathione levels in human subjects.1 Even though this study was published in 1992, there is no credible evidence that this has changed. The authors concluded, “it is not feasible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3000 mg of glutathione ... the systemic availability of glutathione is negligible in humans.” The oral absorption of glutathione is better in rats because the human gastrointestinal tract contains high amounts of the hydrolytic enzyme glutamyl transpeptidase that breaks down glutathione. Furthermore most forms of commercial glutathione and commercial formulations of glutathione products are highly unstable. They are subject to degradation, oxidation and pre-systemic metabolism.

Direct Delivery from the Oral Cavity into the Bloodstream

However, nanosphere interoral delivery can circumvent these problems oral failures of glutathione in two separate ways: First, through the use of a stable form of glutathione, which has now become available, and second, by encapsulating stable glutathione in protective-stabilized nano-sized vesicles. Thus, it is now possible to delivers protected glutathione into the bloodstream directly through the oral mucosa and intracellularly to target cells. The ability of a protected, stabilized encapsulated glutathione, compared with non-encapsulated glutathione for replenishment of intracellular levels was 100-fold more potent as a source for intracellular glutathione repletion.2

Natural phospholipids are used to encapsulate glutathione in protective stabile nano-sized bilayer spheres that mimic plasma lipoproteins. These tiny stable nanosphere structures with an average particle size of 14 nm can carry protected glutathione directly from the mouth to the blood stream via transmucosal absorption into jugular vein for systemic distribution and across cell membranes to target intracellular sites as well as transport glutathione across the blood-brain barrier into target neural tissues and inside neural cells.

Thus it is now possible to sustain glutathione blood levels, achieve higher-potency responses, increase the circulatory half-life, and enhance site-specific bioactivity. Furthermore, it has the ability to replenish intracellular glutathione, transport glutathione across the blood-brain barrier, and provide neuroprotection.

Research Shows Increase Glutathione Blood Levels up to 34%

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Nanosphere intraoral delivery systems have been proven to increase glutathione blood level in human subjects up to 34% in less than 45 minutes.3 Healthy subjects were given an intraoral oral dose of 1 gram of GSH by administering 100 mg increments of GSH between their gums and cheeks over a period of 5 minutes through a precision 0.5 ml dose-metering pump. Venous blood samples were drawn from the antecubital vein. Total glutathione (tGSH) and GSSG (the oxidized form of glutathione, glutathione disulfide) were measured by the enzymatic method of Tietze, which was modified. The content of glutathione was calculated as the difference between tGSH and GSSG, the figures for which are shown for test subjects in the graph above and the table below. The test data suggests an optimal dosage administration of every 3 hours that corresponds with the consensus of GSH half-life studies.

The findings of this study indicate that a properly-formulated nanosphere intraoral delivery system sustains glutathione blood levels, achieves higher-potency responses, increases the circulatory half-life, and enhances site-specific bioactivity. Furthermore, it has the ability to replenish intracellular glutathione, and transport glutathione across the blood-brain barrier, thus providing neuroprotection.

References

  1. Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992;43(6):667-9.
  2. Zeevalk GD, Bernard LP, Guilford FT. Liposomal-glutathione provides maintenance of intracellular glutathione and neuroprotection in mesencephalic neuronal cells. Neurochem Res 2010 Oct;35(10):1575-87.
  3. In-house study from Quicksilver Scientific.

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