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| Home » Nutritional Library » ImmunoPro RX |
ImmunePro Rx - The Finest Biologically Active ProteinIn a Class of its Own - Lab Verified PotencyNaturally Contains The Highest Levels of Undenatured Lactoferrin, Immunoglobulins, Active Peptides and Growth Factors.A primary product of milk.
ImmunoPro Rx Whey Protein Concentrate is unique. It is a Primary-Product of Fresh Milk. It is not a by-product. It is the result of years of work to perfect a system that produces only the highest quality milk whey protein. There is no cheese produced in any part of our production. There is no chemical modification or pH regulation in the milk or whey. The full range of the original proteins is intact and undenatured. The result is a superior product that contains exceptional amounts of the most important protein fractions. Additionally the vital proteins bound fats that whey protein isolates remove are still intact. Traditionally, even the most expensive
dietary whey products available are the by-products of cheese production
with definite limitations
in preserving the complete biological activity of the whey proteins.
The milk goes through
a heating process (approx. 163° F), chemical modification and pH regulation
to produce cheese. Each of these steps denatures (damages) the whey
proteins. The denatured proteins are then filtered out and what remains
is a narrow
range of undenatured proteins that have survived the processing.
From this point on there is little heat added and some of these whey protein
isolates
are then referred to as cold process. The Importance of Cysteine vs. CystineBiologically active whey protein that contains naturally occurring Cysteine is the optimal component for the intracellular production of Glutathione (GSH). Cysteine is very scarce in our modern diet and therefore Glutathione production is limited and deficiency is prevalent. If Cysteine undergoes any heating or processing, as all conventional dairy and dairy by-products do, it is denatured and converted to Cystine. Cystine is the form that is found in all of the medical food whey proteins, as they are all by-products. ImmunoPro Rx is unique as it is a Primary-Product and contains naturally occurring Cysteine. An important note on the synthesized free form amino acid L-Cysteine, it can have adverse effects in supplemental doses with sensitive individuals or those who have any heavy metal accumulation. The Journal of the American College of Nutrition Volume 5, 1986, published a paper by Anderson and Meister titled "Intracellular Delivery of Cysteine and Glutathione Delivery Systems." It concluded that when subjects were fed naturally occurring Cysteine, it gave them significantly more production of Glutathione than when fed Cystine. Eleven times more. Regarding Whey Protein Concentrate: The journal Immunology 61: 503-508, 1987 reports, The bioactivity occurs through the ability of the protein concentrate to help replenish Glutathione levels via continuous dietary provision of Glutathione precursors, especially Cysteine, during lymphocyte proliferation, thus supporting an optimal immune response. This process seems to not only increase intercellular levels of Glutathione and precursors at the time of ingestion, but also builds up stores of these substances within the cells which lasts for a substantial post-ingestion time interval. " ImmunoPro Rx is the only True Nondenatured Biologically Active Whey Protein. It is a Primary-Product and contains the full range of naturally occurring protein fractions. It contains the highest levels of Lactoferrin, Immunoglobulins, and Serum Albumin. Laboratory verified* as many times higher than the leading whey protein products. These three protein fractions contain exceptional amounts of Cysteine and Glutamine, the precursors required for the production of intracellular Glutathione. ImmunoPro Rx contains the following protein fractions.
|
FRACTION |
DAMAGED BY |
Beta-Lactoglobulin |
Reasonably stable |
Alpha-Lactalbumin |
Partially denatured by acid pH conditions |
Glycomacropeptides |
Adjustment of pH |
Immunoglobulins (IgG) |
Acid pH and heat (destroyed at 140 degrees F |
Bovine Serum Albumin |
Heat treatment (damaged at 162 degrees F) |
Lactoferrin |
Acid pH and heat (totally destroyed at 152 degrees F) |
Growth Factors |
Any processing, as they are contained in the fat globule membrane. |
Cysteine, the amino acid, is naturally present in raw milk. Cysteine is the undenatured biologically active form of Cystine. Cystine is formed after the heating and pH adjustment raw milk goes through in cheese production. All by-products have the Cystine form. Up until January 2000 all whey proteins available have been by-products of cheese production.
Let's get this straight. Water solubility does not equate to denaturation! Water solubility only shows that the process did a good job of removing the denatured whey proteins during processing. What the consumer gets from the "un-denatured" whey proteins from cheese and casein (which is where all the industry's whey comes from) is not even strictly a whey protein. In order to be a whey protein, all of the protein fractions have to be represented in the ratios and amounts that would be expected in unprocessed milk. Such is not the case with the whey proteins coming out of the cheese and casein factories. The best fractions are gone, or have been significantly destroyed and removed.
Pretty depressing stuff, eh? Basically, for the last couple of months, I've been telling you about all the amazing properties of whey, only to now have to inform you that today's commercial protein supplements are devoid of the bioactive ingredients responsible for these properties. Don't get too depressed; supplements produced by some of the better CFM facilities still contain a small degree of some of the fractions and are still quality proteins with pretty good digestibility.
Unfortunately, if you can imagine the quantity of whey that goes into agriculture (animal feeds), infant formulas and clinical nutrition (enteric feeds, etc.), you will realize that bodybuilding supplements represent an almost negligible percentage of the worldwide market. In fact, bodybuilding supplements represent only a small percentage of the supplement industry! Therefore, the likelihood of a company putting in the time, expense and resources necessary to develop a product that fits the previously mentioned ideal is remote until now.
This has resulted in a company producing a whey protein concentrate under the ideal criteria (i.e., from milk production and with low temperature pasteurization). The end products made from these materials are intended for the medical industry-in particular, AIDS victims and sufferers of cancer, Chronic Fatigue Syndrome and conditions of the intestinal tract, such as ulcerative colitis.
The good news is that one nutrition company is now including these materials in their MRPs and protein powders. I hope this series has helped you understand what you should be looking for in a protein supplement and provided you with a little consumer protection from unscrupulous marketing.
There is no rBST, rBGH, hormone treatment or GMO feed history with our cows, ImmunoPro( Rx, Sero WPC, Organic Colostrum or any of our products. The use of genetically engineered rBST/rBGH, common hormone treatment in milk cows, is an issue to be reckoned with. The United States is the main country where it is legal. The educated consumer is questioning the use of hormones and is becoming aware that this may not be a natural or safe way to produce milk. After thorough review, Europe and Canada banned hormone treatment in milk production for human consumption products. The use of GMO feeds is also a major concern. Our customers from the US, Europe, Asia, and the UK frequently inquire about the use of hormones and voice concern about the long-term health implications. New findings on the consumption of genetically engineered organisms and their effects on the immune system are not encouraging.
Contrary to common thought, there are several different hormones given to cows in a conventional dairy. Lutalys (Prostaglandin F2d) is used to bring a cow into heat (able to be impregnated), GNRH is given to treat cystic ovarian disease in higher producing cows and Oxytocin to stimulate milk let-down. Bovine growth hormone (also known as rBST and rBGH) is a genetically engineered hormone in use on US cows and utilized to increase milk production. The use of hormones and GMO feed is legal in conventional dairies. Neither the State nor Federal government does testing for hormones. Use of hormones is illegal on certified organic dairies. Organic and natural dairies rely on the cow's own natural health to produce quality milk.
So the truth is, it is very profitable for any dairy farmer with more than 100 cows to use these milk-producing hormones. With one hormone injection per month there is a 15% increase in milk production with no other expenditures. That 15% increase in production equates to raising the dairies net profit three fold. A non-organic conventional whey product cannot honestly claim to be Hormone Treatment free or GMO Feed free unless they have complete control over the treatment of the cows.
The reality is hormone treatment and GMO feed is legal in the US. It cannot be detected and a high percentage of the dairies in all states use hormones and it is kept quiet. The manufacturers of cheese and whey downplay its use because they pool milk from many conventional farms and cannot verify treatment. The FDA sanctions its use even though the consumer questions it. US dairy owners are the wealthiest in the world because of their high yield cows. This fact is not highly publicized.
*The milk for all of our exclusive milk protein products is derived from herds that graze on disease-free, pesticide-free, chemical free, natural grass pastures. The milking cows are not subject to any chemicals, hormones, antibiotics, genetically modified organisms, hyperimmunization or injected pathogens. They do not ingest any unnatural man-made substances. There is no history of bovine disease with our milk cows or dairy. Our cows have never been fed any imported food or cannibalistic by-products. I trust this will help you see the bigger picture on milk and why Wellwisdom is committed to providing the finest quality natural products.
Reduced glutathione, most commonly called glutathione or GSH, is a relatively small molecule ubiquitous in living systems. Occurring naturally in all human cells, GSH is a water-phase orthomolecule. Its intracellular depletion ultimately results in cell death and its clinical relevance has been researched for decades.
GSH is the smallest intracellular thiol (SH) molecule. Its high electron-donating capacity (high negative redox potential) combined with high intracellular concentration (millimolar levels) generate great reducing power. This characteristic underlies its potent antioxidant action and enzyme cofactor properties, and supports a complex thiol-exchange system, which hierarchically regulates cell activity.
GSH levels in human tissues normally range from 0.1 to 10 millimolar (mM), most concentrated in the liver (up to 10 mM) and in the spleen, kidney, lens, erythrocytes, and leukocytes.5 Plasma concentration is in the micromolar range (approx. 4.5 µM). Oxidative stressors that can deplete GSH include ultraviolet and other radiation; viral infections; environmental toxins, household chemicals, and heavy metals; surgery, inflammation, burns, septic shock; and dietary deficiencies of GSH precursors and enzyme cofactors.
Reduced glutathione (GSH) is a linear tripeptide of L-glutamine, L-cysteine, and glycine. Technically N-L-gamma-glutamyl-cysteinyl glycine or L-glutathione, the molecule has a sulfhydryl (SH) group on the cysteinyl portion, which accounts for its strong electron-donating character. As electrons are lost the molecule becomes oxidized, and two such molecules become linked (dimerized) by a disulfide bridge to form glutathione disulfide or oxidized glutathione (GSSG). This linkage is reversible upon re-reduction. GSH is under tight homeostatic control both intracellularly and extracellularly. A dynamic balance is maintained between GSH synthesis, its recycling from GSSG/oxidized glutathione, and its utilization.
GSH synthesis involves two closely linked, enzymatically controlled reactions that utilize ATP. First cysteine and glutamate are combined, by gamma-glutamyl cysteinyl synthetase. Second, GSH synthetase combines gamma-glutamylcysteine with glycine to generate GSH. As GSH levels rise, they self-limit further GSH synthesis; otherwise, cysteine availability is usually rate-limiting. Fasting, protein-energy malnutrition, or other dietary amino acid deficiencies15 limit GSH synthesis.
GSH recycling is catalyzed by glutathione disulfide reductase, which uses reducing equivalents from NADPH to reconvert GSSG to 2GSH. The reducing power of ascorbate helps conserve systemic GSH.16 GSH is used as a cofactor by
GST underactivity may increase risk for
disease
but
paradoxically, some GSH
conjugates can also be toxic.
Direct attack by free radical and other oxidative agents can
also deplete GSH. The homeostatic glutathione redox cycle attempts
to
keep GSH repleted
as it
is being consumed. Amounts available from foods are limited
(less than 150 mg/day), and oxidative depletion can outpace
synthesis.
The liver is the largest GSH reservoir. The parenchymal cells synthesize GSH for P450 conjugation and numerous other metabolic requirements, then export GSH as a systemic source of SH/reducing power. GSH is carried in the bile to the intestinal luminal compartment. Epithelial tissues of the kidney tubules, intestinal lining, and lung, have substantial P450 activity and modest capacity to export GSH.
GSH equivalents circulate in the blood predominantly as cystine, the oxidized and more stable form of cysteine. Cells import cystine from the blood, reconvert it to cysteine (likely using ascorbate as cofactor), and from it synthesize GSH. Conversely, inside the cell GSH helps re-reduce oxidized forms of other antioxidants such as ascorbate and alpha-tocopherol.
GSH is an extremely important cell protectant. It directly quenches reactive hydroxyl free radicals, other oxygen-centered free radicals, and radical centers on DNA and other biomolecules. GSH is a primary protectant of skin, lens, cornea, and retina against radiation damage, and the biochemical foundation of P450 detoxication in the liver, kidneys, lungs, intestinal epithelia, and other organs.
GSH is the essential cofactor for many enzymes which require thiol-reducing equivalents, and helps keep redox-sensitive active sites on enzymes in the necessary reduced state. Higher-order thiol cell systems the metallothioneins, thioredoxins, and other redox regulator proteins are ultimately regulated by GSH levels and the GSH/GSSG redox ratio. GSH/GSSG balance is crucial to homeostasis, stabilizing the cellular biomolecular spectrum, and facilitating cellular performance and survival.
GSH and its metabolites also interface with energetics and neurotransmitter syntheses, through several prominent metabolic pathways. GSH availability down-regulates the pro-inflammatory potential of leukotrienes and other eicosanoids. Recently discovered S-nitroso metabolites, generated in vivo from GSH and NO (nitric oxide) further diversify GSH's impact on metabolism.
Glutathione status is a highly sensitive indicator of cell functionality and viability. As intracellular GSH becomes reduced, the cell's functionality is progressively reduced until it dies. In humans, GSH depletion is linked to a number of disease states.
Individuals
with inherited deficiencies of the GSH-synthesizing enzymes exhibit
limited or generalized GSH deficiency,
with hemolytic
anemia, spinocerebellar degeneration, peripheral neuropathy, myopathy,
and aminoaciduria, and often develop severe neurological complications
in the fourth
decade of life. These conditions are not necessarily lethal because
of
their incomplete penetrance; in some tissues GSH can attain 50 percent
of normal.
In addition, some GSH is obtained from the diet. Low erythrocyte
GSH also manifests in hereditary nonspherocytic lymphocytic leukemia,
and
glucose-6-phosphate
dehydrogenase (G6PD) deficiency.
HIV Infection/Immunity: Immune cell functionality and proliferation
rely on adequate intracellular GSH, and healthy humans with low
lymphocyte
GSH can
have low CD4 counts. HIV infection and sequelae feature systemic
GSH depletion. Oxidative stress is elevated at all stages of HIV
disease;
HIV infection
lowers GSH in the plasma, erythrocytes, T-cells and other lymphocytes,
and monocytes.
Children with HIV also demonstrate low plasma GSH. The cachexia
and wasting of AIDS may be amenable to GSH repletion. HIV depletion
of lung
epithelial
lining fluid (ELF) glutathione may predispose to opportunistic
infections, and the ELF may be repleted using aerosolized GSH.
Plasma and erythrocyte GSH can be low in patients with cirrhosis or result from acute or chronic alcohol intake. In nonalcoholic liver disease, liver GSH can be abnormally low and GSSG high. Acetaminophen and other pharmaceutical or environmental xenobiotics can deplete liver GSH. Viral hepatitis can deplete GSH, and in hepatitis C patients monocyte GSH has been found to be depleted.
GSH deficiency has been linked to various pulmonary diseases, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), neonatal lung damage, and asthma. The lung is particularly vulnerable to oxidative attack from inhalation of pure oxygen, airborne toxins, and oxygen radical release by lung phagocytes. GSH in lung ELF may be the first line of defense.
The GSH content of ELF was found abnormally low in idiopathic pulmonary fibrosis, ARDS, and HIV-positive patients. ARDS patients with sepsis had low GSH and high GSSG in their ELF. GSH repletion can accelerate ARDS patient release from intensive care. GSH in the ELF can be lifesaving for premature infants. Pulmonary GSH levels have been found to be low in premature infants, and in perinatal hypoxia cases umbilical blood GSH has also been found to be low. Newborns with low GSH in the ELF may be at higher risk of chronic lung disease.
Gastric mucosa of aged subjects can have low GSH, as can patients with gastritis and/or duodenal ulcer linked to Helicobacter pylori infection. In Crohn's disease cases the affected ileal zones were found to have low GSH and high GSSG, and GSH enzymes were altered.
Acute myocardial infarction patients and men with familial coronary artery disease exhibit lowered GSH. Glutathione given i.v. prior to cardiopulmonary bypass surgery favorably influenced postoperative renal function while improving systemic arterial function.
Infusion of GSH into patients with atherosclerosis enhanced microvascular vasodilation in response to acetylcholine, especially in subjects with baseline abnormal vessel wall reactivity.30 Similar benefits were reported for the epicardial coronary artery system. S-nitrosoglutathione also has platelet anti-aggregation activity in humans, as reviewed in Prasad et al. The mechanism of vasodilation is suspected to be via glutathione's enhancement of nitric oxide.
In several copper-overloaded (Wilson's Disease) patients, hepatic GSH was markedly lowered. This preliminary finding correlates with an impressive body of animal data.
Plasma GSH was significantly lowered in chronic pancreatitis linked to alcohol intake, and patients with acute pancreatitis responded well to glutathione repletion.
Subjects with impaired glucose tolerance, including early hyperglycemics, had reduced blood GSH. In diabetics, the erythrocytes and platelets can be low in GSH. Mild to moderate exercise can help normalize GSH status in diabetics, although strenuous exercise can deplete GSH.
A variety of neurodegenerative diseases manifest
abnormally low GSH. In Alzheimer's a decrease
in lymphoblast
GSH has been reported. In Parkinson's disease the substantia nigra
becomes greatly depleted of GSH.
The threshold of GSH depletion, below which the cell will usually die,
is 70-80 percent. The mitochondria, with their high oxygen radical
flux, are particularly
vulnerable. Mitochondrial failure has been specifically implicated
in retinal degeneration7 and in Parkinson's disease.
The aging process is associated with deterioration of GSH homeostasis. Plasma GSH trends lower while GSSG becomes more elevated. Limited data suggests higher GSH levels correlate with better health, regardless of age, and that subjects with chronic disease have poorer GSH status than those free of disease. Exercise training can strengthen GSH homeostasis. With progressively more disease states manifesting GSH deficiency, repletion is a viable preventive, therapeutic, and anti-aging strategy.
Tradition holds that GSH is not systemically bioavailable when given by mouth. However, copious data confirm it is efficiently absorbed across the intestinal epithelium, by a specific uptake system. Catabolism of newly-absorbed GSH after it reaches the portal blood intact but prior to its accessing the liver accounts for the paradoxical findings. Such breakdown of circulating GSH does not rule out its oral use for GI conditions such as Crohn's Disease.
Results from two controlled trials seem to suggest oral GSH had no significant benefit, but do not rule out benefit from high-dose GSH to depleted subjects. In one trial, the plasma concentration was high-normal at baseline. In the second, the dose administered (to cirrhosis patients), at 300 mg/day for 28 days, may have been insufficient to replete liver GSH in the context of severe impairment of biosynthesis.
Chronic, low level exposure to toxic metals is an increasing global problem. The symptoms associated with the slow accumulation of toxic metals are multiple and rather nondescript, and overt expression of toxic effects may not appear until later in life. The sulfhydryl-reactive metals (mercury, cadmium, lead, arsenic) are particularly insidious and can affect a vast array of biochemical and nutritional processes. The primary mechanisms by which the sulfhydryl-reactive metals elicit their toxic effects are summarized. The pro-oxidative effects of the metals are compounded by the fact that the metals also inhibit antioxidative enzymes and deplete intracellular glutathione. The metals also have the potential to disrupt the metabolism and biological activities of many proteins due to their high affinity for free sulfhydryl groups. Cysteine has a pivotal role in inducible, endogenous detoxication mechanisms in the body, and metal exposure taxes cysteine status. The protective effects of glutathione and the metallothioneins are discussed in detail. Basic research pertaining to the transport of toxic metals into the brain is summarized, and a case is made for the use of hydrolyzed whey protein to support metal detoxification and neurological function. Metal exposure also affects essential element status, which can further decrease antioxidation and detoxification processes. Early detection and treatment of metal burden is important for successful detoxification, and optimization of nutritional status is paramount to the prevention and treatment of metal toxicity. Altern Med Rev 1998;3(4):262-270.Introduction
Globally, food, water and the environment have deteriorated to the point that we are all vulnerable to at least chronic, low level exposure to toxic metals. In the United States it has been revealed that tons of toxic industrial wastes, including heavy metals, are being mixed with liquid agricultural fertilizers and dispersed across America's farmlands. Although the practice of dispersing arsenic, lead, cadmium, nickel, mercury, and uranium on soil and pastures is currently a controversial political and economic issue, the potential for long-term adverse health effects is obvious and well documented.
The primary objective of this review is to highlight the general effects of toxic metals on biochemical and nutritional processes, and provide rationale for appropriate therapeutic intervention. Knowledge of the mechanisms by which toxic metals affect a vast array of metabolic processes will help clarify why the symptoms of metal burden are numerous and nondescript. Increased awareness might help in the successful treatment of the difficult-to-diagnose patient.
Acute metal toxicity as a result of occupational/industrial exposure can be readily diagnosed by means of patient history and overt symptoms. However, the more subtle effects of chronic, low-level exposure are associated with rather nondescript symptoms, and overt expression of physiological aberrations are often not realized until later in life. This is particularly apparent for the neurotoxic effects associated with the sulfhydryl-reactive metals.
Among the most insidious toxic metals are the sulfhydryl-reactive metals, which include mercury (Hg), cadmium (Cd), lead (Pb), and arsenic (As) and this review will focus on these metals; their common toxicity symptoms are summarized in Table 1. Despite considerable overlap in symptoms associated with accumulation of these metals in the body, it is clear that the metals do vary somewhat with respect to primary sites of deposition. For example, Hg and Cd are deposited heavily in the kidneys; in fact, the biological half-life of Cd in the kidneys is on the order of decades. However, unlike Hg, Cd does not readily cross the blood brain barrier in adults and, in contrast to Hg, Cd is associated more with peripheral neuropathy than disorders of the central nervous system. Lead is deposited primarily in bone, and disrupts erythropoiesis. It is beyond the scope of this review to discuss in detail the neurotoxic, nephrotoxic, fetotoxic and teratogenic effects of the metals; a comprehensive review of these topics is presented by Chang. The metals presented in Table 1 are systemic toxins that may well be the underlying cause of persistent ill health in patients presenting with chronic symptoms of fatigue, musculoskeletal pain, neurological disorders, depression, poor cognitive function and memory, and allergic hypersensitivity.
Biochemical Aspects of Metal Toxicity
What are the primary biochemical processes disrupted by the sulfhydryl-reactive metals? This question is best answered by focusing on mercury, which has been the subject of extensive basic research. Much of what has been learned about the toxic effects of mercury holds true for other sulfhydryl-reactive metals, due to similarities in chemical reactivity. However, it is important to note that mercury is much more volatile than other sulfhydryl-reactive metals and therefore it is more highly absorbed in the elemental (Hg0 ) form. An excellent review of the literature pertaining to the toxicity of Hg0 from dental amalgams has been presented by Lorscheider et al.
The primary sources of chronic, low-level Hg exposure are dental amalgams and fish. Hg enters water as a natural process of off-gassing from the earth's crust and as a result of industrial pollution. Mercury is methylated by algae and bacteria in water and moves up the food chain to highest concentrations in large predatory fish such as swordfish, shark, salmon and tuna. Other sources of Hg include the combustion of fossil fuels, and the production of chlorine, paper and pulp, fungicides/seed preservatives, and some paints. In some parts of the world, large amounts of Hg enter the environment as a result of careless processing of gold from ore. For example, the water, fish and local inhabitants of the Amazon River are greatly affected by the indiscriminate use of Hg in the mining of gold in Columbia.
The two major, highly absorbed subspecies of Hg are elemental Hg0 and methyl-mercury (MeHg). Figure 1 illustrates the processes of assimilation of these two species of Hg. So-called "silver dental amalgams" contain over 50 percent Hg0, which is volatile and vaporizes at room temperature. Although Hg0 is poorly absorbed if ingested, Hg0 vapor is efficiently absorbed through the lungs and quickly passes the blood-brain barrier. Due to its lipophilic nature, Hg0 has a high affinity for myelin and lipid membranes. Once inside a cell, Hg0 is oxidized by catalase to the highly reactive Hg2+. MeHg, derived from fish, and dimethylmercury are readily absorbed in the gastrointestinal tract. MeHg can be de-methylated and oxidized to Hg2+. Once assimilated in the cell, Hg2+ and MeHg+ form covalent bonds with glutathione and the cysteine residues of proteins. The adverse effects of metal binding to sulfhydryl groups will be discussed below in detail.
Once absorbed, Hg has a low excretion rate. A significant proportion of the assimilated Hg is retained and continually accumulates in the kidneys, neurological tissue (including the brain), and the liver. Upon autopsy, high levels of Hg have also been found in cardiac, thyroid, and pituitary tissues of dentists. The overt neurotoxic and nephrotoxic effects of high-level Hg exposure are well established, but the more subtle effects of chronic, low- level Hg ac-cumulation appear to be vast and nondescript.
The sulfhydryl-reactive metals have three major properties which mechanistically explain how they elicit a majority of their toxic effects. First, they are transition metals that promote the formation of hydrogen peroxide and enhance the subsequent iron- and copper-induced production of lipid peroxides and the highly reactive hydroxyl radical. Lipid peroxides alter membrane structure and are highly disruptive of mitochondrial function.
The pro-oxidant properties of the metals are exacerbated by their inhibitory effects on antioxidant processes. Hg and Cd have high affinities for glutathione (GSH), which is the primary intracellular antioxidant and conjugating agent. Importantly, a single atom of Cd or Hg can bind to, and cause the irreversible excretion of, up to two GSH tripeptides. The metal-GSH conjugation process is desirable in that it results in the excretion of the toxic metal into the bile. However, it can deplete the cell of GSH and thus decrease antioxidant capacity. Lead-induced depletion of intracellular GSH and increased levels of malondialdehyde in brain and liver have been demonstrated in animal models. It has also been demonstrated that Hg not only directly removes GSH from the cell, but also inhibits the activities of two key enzymes involved in GSH metabolism: GSH synthetase and GSH reductase. Hg also inhibits the activities of the free radical quenching enzymes catalase, superoxide dismutase,16 and perhaps GSH peroxidase. The inhibition of GSH peroxidase has been attributed to the formation of a mercury-selenide complex. Selenium is an integral component of GSH peroxidase.
In addition to promoting lipid peroxidation, depleting GSH and inhibiting antioxidative processes, the sulfhydryl-reactive metals disrupt the structure and function of numerous important proteins through direct binding to free sulfhydryl groups. Intact sulfhydryl groups are critical for the biological activities of virtually all proteins, including Na/K ATPase. Metal-induced inhibition of Na/K ATPase can result in astrocytic swelling and destruction; astrocytes are the primary cells responsible for the homeostatic regulation of synaptic pH, Na/K and glutamate, and metal sequestration in the CNS.
Recent studies clearly illustrate how destructive the interaction between Hg and sulfhydryl groups can be. Hg inhibits the polymerization of tubulin, causes depolymerization of existing microtubules, and in animal studies results in brain lesions that closely resemble those found in patients with Alzheimer's Disease. Adaptive Responses to Metal Toxicity
The body makes important adaptive changes in response to exposure to sulfhydryl-reactive metals. Recent studies in rats illustrate the importance of GSH metabolism in the presence of Hg exposure. Short and long-term exposure to MeHg in drinking water resulted in a two- to three-fold up-regulation of mRNA encoding for g-glutamylcysteine synthetase, which is the rate-limiting enzyme in GSH synthesis. Figure 2 illustrates the enzymes, amino acids, and co-factors involved in GSH biosynthesis. Concomitantly there was a similar magnitude of increase in the steady state levels of GSH, and the activities of GSSH reductase and GSH peroxidase. These data illustrate a protective, adaptive response to Hg exposure in renal epithelial cells. Neurons do not appear to have such adaptive capacity which may partially explain why Hg is relatively more neurotoxic then nephrotoxic.
A second adaptive and protective response to toxic metal exposure is induction of metallothionein synthesis. Metallothioneins are a fascinating group of low molecular weight, intracellular proteins that serve as a storage depot for copper and zinc, and "scavenge" sulfhydryl-reactive metals that enter the cell. Metallothioneins across species are rich in cysteine (~30%) and have higher affinities for Hg and Cd than for zinc. Therefore as Hg and Cd bind to metallothionein, and are restricted from entering the mitochondria, zinc is released. The free, ionized zinc, which would be toxic if permitted to accumulate, binds to a metal regulatory element on the promoter region of the metallothionein gene and "turns on" the synthesis of metallothionein. Such induction of metallothionein provides increased binding capacity for both toxic metals (protective) and zinc (functional). The displacement of zinc in the presence of toxic metal burden may explain in part why increased levels of zinc are so commonly seen in the scalp hair of patients exhibiting significant levels of toxic metals Hg, Cd, Pb (Quig, unpublished observations).
The importance of metallothionein in the protection against toxic metals is evident. Mammalian cell lines with the greatest number of copies of the metallothionein gene and the highest levels of metallo-thionein survived exposure to Cd in culture media. MT-null mice, genetically engineered to have inactivated metallo-thionein genes, died within three days of exposure to Cd in drinking water, while control (normal) mice did not exhibit any signs of Cd toxicity. Rat pups exposed to Hg vapor in utero were born with higher levels of metallothionein mRNA and metallothionein levels in astrocytes. Metallothionein levels were also found to be induced in primary astrocyte cultures by CdCl2 and MeHg. The induction of metallothionein in astrocytes is very important in protecting the CNS since neurons cannot up-regulate GSH or metallothionein synthesis in response to metal exposure.Cysteine, Leucine, and Mercury Transport Across the Blood-Brain Barrier
It is clear from the preceding discussion that cysteine, a conditionally essential amino acid, can be depleted with the chronic stress of metal burden. Cysteine becomes a pivotal factor to support detoxification and the body's attempt to produce more GSH and metallothionein.
How should one supply cysteine to a patient who has toxic metal accumulation? Experimental evidence from animal studies clearly indicates supplementation of cysteine at high doses can actually increase the transport of Hg into the brain. Pregnant rats received intravenous infusions of saline, L-cysteine, L-leucine, or GSH prior to infusion of MeHg. Although total body Hg was similar for all groups of pups and dams, brain Hg concentrations were significantly increased in dams and pups given cysteine. In contrast, brain Hg levels were lower for the animals receiving intravenous GSH. In subsequent studies it was clearly demonstrated that the mechanism for transport of MeHg across the blood brain barrier is the large neutral amino acid (LNAA) transport system, also known as the L (leucine-preferring) system. Based on these studies, it is suggested high doses (e.g. 500 mg three times daily) of cysteine (as L-cysteine or N-acetylcysteine) in a metal-burdened patient can facilitate redistribution of Hg from tissues and organs throughout the body into the brain, where it elicits its insidious neurotoxic effects. It should be noted intravenous administration of GSH had protective effects on brain Hg accumulation, but it cannot be assumed high doses of GSH administered orally would have the same beneficial effect, due to the potential for hydrolysis of GSH in the gastrointestinal tract.
L-leucine inhibits transport of the MeHg-cysteine complex across the blood brain barrier.31,32 Therefore, it seems prudent to provide small amounts of cysteine in conjunction with sufficient quantities of leucine and the other amino acids which compete for the L-amino acid transport system, including valine, isoleucine, phenylalanine, tyrosine and tryptophan. Whey protein, derived from milk, contains about 2.5_3.0 percent cysteine/cystine and about 22 to 25 percent branched-chain *amino acids.33 Therefore, a high quality undenatured whey protein product provides a good source of cysteine to support intracellular GSH production and metallothionein synthesis, yet adequate leucine to minimize the transport of metals into the CNS. Low temperature appears to be the preferred method of production. It is noteworthy that undenatured whey protein has been reported to enhance immune function.34 An alternative to whey protein might be to provide reasonable amounts of N-acetylcysteine (200-300 mg daily) with a relatively high (quantity and quality) protein diet. The important point here is that pharmacological doses of cysteine/NAC, in the range of 1500 mg daily, have the potential to exacerbate the adverse neurological effects of toxic metals. Note: He has revised that caution to ingesting no more than 500 mg NAC.
Provision of cysteine/cystine in a complete, balanced source of protein will also provide important amino acids that are precursors to neurotransmitters. Cell studies indicate Hg exposure directly affects uptake and release of dopamine, norepinephrine, and serotonin.35 Indirectly, Hg burden can be associated with depletion or poor assimilation of specific amino acids which are precursors of neurotransmitters. For example, taurine is a neurotransmitter derived from methionine/cysteine. As discussed, available pools of these sulfhydryl amino acids can be depleted by the metal-induced high turnover of GSH. Persistent candidiasis/dysbiosis associated with Hg burden can compromise the absorption of aromatic amino acids such as phenylalanine/tyrosine and tryptophan, which are precursors to dopamine/norepinephrine and serotonin, respectively (Quig, unpublished observations).Possible Endocrine Involvement
The endocrine system (the master regulator of metabolism) is also affected by Hg burden. Like cadmium, Hg inhibits the conversion of thyroxine (T4) to active T3. It has been suggested the metal-induced inhibition of the 5'deiodinase enzyme is related to general peroxidative effects; however, the inhibition by Hg may be more specific. Hg is known to irreversibly bind to and "waste" selenium, and 5'deiodinase is a selenium-dependent enzyme. Therefore, Hg may inhibit the conversion of prohormone T4 to T3 by interfering with selenium availability.
Hg may also interfere with progesterone metabolism without affecting serum levels of progesterone. In vitro studies indicate Hg binds to a free sulfhydryl group on the progesterone receptor and may thereby diminish progesterone binding and cellular response.38 The aforementioned Hg-induced disruptions in hormone metabolism could certainly contribute to chronic fatigue, which is one of the hallmark features of Hg burden. Another possible link of metal toxicity to chronic fatigue is via metal binding to the sulfhydryl-containing antioxidant, lipoic acid, making lipoic acid unavailable for its vital role in the energy-producing tricarboxylic acid (citric acid, Krebs) cycle.
Essential element metabolism is also directly affected by toxic metal burden. For example, Hg and Cd readily displace zinc and copper from metallothionein, which serves as the intracellular "sink" for these essential elements. Copper and zinc are co-factors for superoxide dismutase, and copper is required for the synthesis of catecholamines. Zinc is also critical for wound healing, immune function and the metabolism of protein and nucleic acids. As discussed, Hg binds and "wastes" selenium, which is an integral constituent of free radical protection (GSH peroxidase). Ethylenediamine tetraacetic acid (EDTA) and the dithiol complexing agents have affinities for Cu, Zn, Mn, Cr and Mo, and can indirectly result in Mg depletion.39,40 Deficiencies of these essential elements can compound the metal-induced disruption of metabolic processes, and further diminish the body's capacities for detoxification and the quenching of excess free radicals.
It is beyond the scope of this review to thoroughly address the appropriate use of the various metal detoxification agents such as EDTA, dimercaptosuccinic acid (DMSA) and dimercaptopropane sulfonate (DMPS). For thorough coverage of these agents see references. An important point should be emphasized, however, regarding the potential for DMSA to contribute further to cysteine depletion. Ninety percent of the DMSA absorbed is excreted in the urine as a cysteine-DMSA-cysteine disulfide complex. Therefore, between days of oral administration of DMSA it is important to replace cysteine, preferably as discussed above. Early detection of metal accumulation is paramount to successful treatment and avoidance of irreversible damage. Hair ele-mental analysis provides a useful screen for the initial detection of toxic metal exposure. A provoked urine elements challenge might then be performed for confirmation, and to establish baseline levels of toxic elements.47 As an alternative to pharmaceutical detoxification agents which mobilize metals through the kidneys, one might choose to perform a pre- and post- fecal metals analysis. Research is in progress to identify and document the efficacy of natural detoxification protocols which facilitate elimination of toxic metals through the natural, biliary (fecal) route. The sulfhydryl-reactive toxic metals have no metabolic function and their accumulation in the body has serious adverse health effects. Metal burden taxes nutritional status, which impacts negatively on antioxidative and detoxification processes. On the other hand, optimization of nutritional status by means of appropriate nutritional support can minimize the daily accumulation, and enhance the excretion, of toxic metals.
Dear Reader,
Dental hygiene is its own reward, of course, but did you know that the health of your gums may have a direct correlation to the health of your heart? This isn't really news - since the late 90's we've seen growing evidence that periodontal disease (an advanced form of gum inflammation) may be linked to an increased risk of heart disease. In fact, later this year the final results are due from a major National Institutes of Health study about the connection between these two disorders.
In the meantime, I recently came across a study that shows how in addition to diligent brushing and flossing, there may be another important way to help keep your gums (and, consequently, your heart) healthy - a method that relies on what we've come to know as one of the primary mainstays of good health: antioxidants.
This study from the University of Birmingham in the UK is small, but I think it's important in that it specifically singles out what could be an effective prevention and treatment of periodontal disease.
The study examined 20 subjects - 10 with healthy gums, and 10 with advanced gum disease. From each subject, researchers took samples of gingival crevicular fluid (GCF), a fluid within the gums that is routinely released from the crevices under the teeth. All of the subjects with healthy gums were shown to have high levels of the antioxidant glutathione, while the subjects with periodontal disease had substantially lower levels of glutathione. When blood serum levels were tested for glutathione, the same disparity was recorded for the two groups.
The fact that this study tested for glutathione (as opposed to any number of other antioxidants) is significant. Last month I sent you an e-Alert ("The Workhorse" 1/9/03) with an in-depth look at glutathione - an enormously effective antioxidant found in every cell of the body, most notably in immune system cells. Glutathione has not only been shown to protect against disease, but may also protect other antioxidants (such as vitamins C and E) from oxidizing, prolonging and enhancing their effectiveness.
But while the UK study results would indicate that boosting glutathione levels might help prevent and control periodontal disease, other questions remain. The researchers wondered, for instance, if lower levels of glutathione directly contribute to gum disease, or if free radicals, produced by gum disease inflammation, depletes the stores of glutathione. The answer may very likely be "yes" on both counts, but we'll have to wait for further research before we have definitive answers.
To me, the word that jumps out here is, "inflammation." A
1997 study from the University of North Carolina at Chapel Hill revealed
that
patients
with advanced gum disease, who had also suffered heart attacks, all
showed significantly higher levels of C-reactive protein (CRP) than
heart attack
survivors who did not have gum disease.
This isn't a surprise, inasmuch as I've explained before that elevated
CRP is a key marker for inflammation. But it does establish further
evidence linking periodontal disease and heart disease. In an e-Alert
I sent you
last
November
("Burst of Inflammation" 11/21/02), I told you about a new
study that showed how the levels of C-reactive protein have been recognized
as
an important marker indicating a risk of heart disease.
Taken together, these studies add further circumstantial evidence to a cycle of cause and effect that goes like this: A low level of the antioxidant glutathione may be associated with periodontal disease - periodontal disease is characterized by inflammation - inflammation brings up CRP levels - elevated CRP levels may indicate a risk of heart disease - a risk of heart disease may be reduced by an increased intake of antioxidants - elevated levels of the antioxidant glutathione may help prevent periodontal disease.
The
upcoming results of more extensive studies (such as the NIH periodontal/heart
disease study) will be needed to further define the gray areas
of this cycle. But for the time being the UK study offers promising
evidence
that antioxidants
(and specifically glutathione) may prove to be an important defense
against periodontal disease.
So, what's the best way to raise glutathione levels? One way NOT
to do it is by oral supplement. Taking glutathione orally is regarded
as ineffective
because
the molecules are too big to pass through the intestinal walls
to the
blood stream.
The food sources that deliver glutathione precursors are meats and fresh fruits and vegetables. But even with a diet high in the proteins that supply glutathione amino acids, one of those amino acids - cysteine - is more difficult than the others to come by. A natural food component with high concentrations of glutathione precursors (including cysteine) is milk-serum-protein concentrate - more simply known as whey.
If you've been diagnosed with periodontal
disease, or if you're currently undergoing treatment for it, share
this information with
all of your
health care providers
- physician, dentist, periodontist - knowing that an important
key to both gum and heart health may be as simple as enhancing
your production
of glutathione
and increasing your intake of other antioxidants.
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