Whey Facts

Lactoferrin
Immunoglobulins
Wellwisdom Whey Proteins Versus Other Whey Proteins 
Bovine Serum Albumin, alpha-lactalbumin and beta-lactoglobulins
Glutathione
Whey Protein Quality As Compared to Other Available Proteins
What is Whey? a report by: David Marshall, Jr., O.D., Ph.D.
Soy Vs. Whey, Carlon M. Colker, M.D. 

Lactoferrin

What is Lactoferrin?
Lactoferrin is an iron-binding and iron-modulating protein found in bovine milk and even more prevalent in our whey protein concentrate. Lactoferrin resides in the chemical family called cytokines. This family of chemicals coordinates the body's cellular immune defensive response that protects us from most infections, tumors and cancers. They also boost the activity of T-cells and stimulate production of immunoglobulins. Without these cytokines our immune system suffers and reacts by creating an over-active immune response. It is our body's first defense, protecting orifices such as the eyes, mouth and nose from bacterial infection.

Lactoferrin and Iron Modulation
Lactoferrin is a very important bioactive molecule which can provide iron to those cells in need, and limit it to those in excess, thus maintaining an iron homeostasis within the body.

Iron deficiency is a fairly common disorder, affecting billions of people a year. The result of iron deficiency can lead to extreme anemia, characterized by fatigue, lethargy, heart palpitations, and shortness of breath. The role of iron in a well functioning body and immune system is well documented and pretty much agreed upon across the board. Common sufferers of iron deficiency include (but are not limited to) women, children, vegetarians, and many studies conclude, high endurance athletes. The body does not easily assimilate iron (or lactoferrin) in a denatured state (highly processed) which is how it is presented in many bovine dietary supplements. With these supplements, high amounts are required for any benefit to arise. Our Proserum® whey protein concentrate is an non-denatured whey protein supplement that is minimally processed to maintain the bioavailability of the lactoferrin.


On the flip side excess iron is a risk as well, although not as common. Some complications associated with this disorder are: bacterial infections, diarrhea, gastrointestinal disorders and even iron-toxicity. A lot of these complications arise from the body's ingestion of unbound iron. Iron that is bound to lactoferrin is much easier to absorb and utilize, and is not lost through human excretions or through other organisms in the body. Iron not bound in the body is a catalyst for the production of free radicals, which have a negative effect on the body's biology. Lactoferrin is an important part of the body's natural defense system. Studies show that it inhibits the binding of pathogens like H. pylori and E. coli to the intestinal wall. Many micro-organisms need iron for growth and by limiting the levels of free iron, lactoferrin can actually inhibit bacterial growth. The pathogens cellular structure loses its integrity because of the iron deprivation and necrosis ensues.


Lactoferrin Studies
The first major entrance of lactoferrin on the health scene was prompted by a paper written by an AIDS researcher discussing the importance of lactoferrin as a regulator of the immune response in people with AIDS. Recent studies have shown that lactoferrin can also inhibit the growth of the HIV virus.


There have been many other studies proving lactoferrin to be a very beneficial substance. The antibacterial properties have been documented very well. A study by the Institute of Public Health in Tokyo, Japan showed that E. coli 0157:H7 can falter under influence of the antimicrobial effects of bovine lactoferrin. Another well documented study by the National Cancer Institute in Tokyo, Japan concluded that bovine lactoferrin inhibits the Hepatitis C infection in human cells. This is of major importance because Hepatitis C has been found to be the main causative factor in chronic viral hepatitis. Lactoferrin seems to inhibit the absorption of the viral particle to the human cell by binding to the cell receptor site or to the virus.


Conclusion
Lactoferrin has a broad range of benefits, with new discoveries being made daily. It enhances and modulates immune system function and provides many iron-enhancing and modulating benefits. It has also been said to act as an immunostimulator in the digestive system, as well as an inhibitor of the growth of many unhealthy micro-organisms in the digestive tract. Lactoferrin regulates the immune response of the body in many differing ways. It inhibits many viruses from thriving in the body and is a very important component in immune-therapy. Our Vital Whey ®, ImmunoPro®, and RenewPro® products provide an excellent source of non-denatured lactoferrin in its most biologically available state.


Immunoglobulins

Immunoglobulins
Immunoglobulins (IgG) are proteins that are present in bovine whey protein. One of their functions is as a transporter of antibodies against harmful microorganisms like viruses, bacteria and other foreign invaders. IgG has been used to treat diseases such as multiple sclerosis, rheumatoid arthritis, hepatitis A, anemia, Chronic Fatigue Syndrome, and chickenpox, among others. IgG are essential elements to maintain a humans immunity from detrimental microorganisms and toxins. This substance is transferred from mother to child inside the womb to protect him/her from the introduction of pathogens in the outside world. This way the child is born with a passive immunity. IgG work together and separately to battle antigens. They circulate in the blood and lymphatic systems, and also reside in the mucous membranes to act as a barrier against invaders.

These immunoglobulins are of a critical importance because many bacteria's become more resistant to antibiotics every day. These bacteria infect our food supply and there are more viruses created at a faster rate than the vaccines used to battle them, science is constantly having to catch up. More and more diseases are being linked to bacterial infection, including peptic ulcers and heart disease.The claim of a link between bacterial infection and heart disorders have very strong evidence to support them(1). ImmunoPro®, with its high amounts of IgG, plays a major role as a supplier of these key protein fractions.


How The Body Utilizes IgG
Our body's first line of immune defense to unhealthy organisms is the intestinal tract(2). The IgG has been found to resist break down by the digestive enzymes within the digestive tract (due to the glycoproteins and trypsin inhibitors), therefore the IgG enters the intestinal wall fully intact where they defend the lining against invading organisms, and prevent the absorption of foreign proteins. The IgG is a factor in increasing the immune system activity level. This substance is important in stabilizing and restoring a damaged intestinal tract so it can function once again at its optimum capacity for nutrient absorption and utilization.


The antibodies derived from bovine milk have many of the mothers milk IgG characteristics and may be active against the same diseases in humans. Immunoglobulins consist of four polypeptide chains with two of the same heavy chains linked by covalent and non-covalent bridges. The light and heavy chains both have areas with constant amino acids and with a variable region. This variable region is where the antibody meets the antigen (foreign molecule). The bovine milk antigens are resistant to the peptic digestion process, which is good for those of us using an non-denatured whey protein abundant in IgG proteins(3).


1. G. Bauriedel, et al.Chlamydia pnuemoniae in coronary plagues. Increased detection with acute coronary syndrome. Dtsch Med Wochenssch 124(13) (April 1, 1999): 37-80; FL Visseren, et al. Atherosclerosis as an infectious disease. Ned Tijdschr Geneeskdl 143(6) (Feb 6, 1999): 291-95; J. Danesch, et al. Is helicobacter pylori a factor in atherosclerosis? J Clin Microbiol 37(5) )May, 1999): 1651; Dp Strachan, et al., Relation of Chlamydia pnuemonia serology to mortality and incidence of ischaemic over 13 years in the caerphilly prospective heart disease study. Br Med J 318(7190) (April 17, 1999): 1035-39; Norman Watner, The Salt lake Tribune June 1, 1996.


2. Guyton AC. Protein Metabolism. In: Textbook of Medical Psyiology 8th edition. Philadephia (PA): WB Saunders; 1991.


3. Watson DL. Immunologic functions of the mammary gland and its secretion - Comparative review. Aust J Biol Sci 1980; 33:402-422


Well Wisdom Whey Proteins Vs Other Whey Proteins

How do Vital Whey®, ImmunoPro® and RenewPro® compare to other whey proteins?

Well Wisdom produces Native* Whey Proteins. They are Biologically Active Full Range Non-denatured Whey Proteins. They are minimally processed to retain all the fragile protein components in their native structures.

Most other whey products are by-products of commercial cheese production and denature the vital immune and regenerative components. They are destroyed from the commercial processing they all undergo.


Vital Whey
®,ImmunoPro® and RenewPro® are the finest native whey proteins available. They contain the full range of the fragile immune modulating and regenerative protein components naturally present in raw milk. They are the result of years of work to perfect a system that produces only the highest quality native whey protein. These superior products contain the highest amounts of the Glutathione precursor covalent bonded Cysteine. Additionally they contain the full range and highest levels of the most important protein components: Lactoferrin, Immunoglobulins, Bovine Serum Albumin, Active Peptides and Growth Factors. 


Traditionally, even the most expensive whey products available (isolates, ion exchange and hydrolyzed) are denatured, overly processed by-products of cheese manufacture. They have definite limitations in preserving the biological activity of the whey proteins. The milk goes through multiple heating steps, chemical modification and pH regulation to produce cheese. Each of these steps damages/ denatures** the whey proteins. The damaged proteins are then filtered out and what remains is a narrow range of undenatured proteins that have survived the manufacturing process. From this point on there is little heat added and some of these whey proteins products are then referred to as "undenatured/ cold processed". It is not possible to undenature a protein.  Also the vital protein bound fats have been removed.

Native Protein is Essential for a Vital Immune System


Vital Whey
®,ImmunoPro® and RenewPro® are the only Full Range Biologically Active Native Whey Proteins.

***They are far more potent than any whey products available. 


The Importance of Cysteine vs. Cystine


Vital Whey®, ImmunoPro® and RenewPro® whey proteins contain exceptional levels of naturally occurring Cysteine. It 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 prolonged heating or processing, as seen with most conventional dairy and dairy by-products do, it is denatured and converted to Cystine. Cystine is the form that is found in high-end whey proteins isolates, as they are all heavily processed to raise their protein content. Vital Whey®, ImmunoPro® and RenewPro® are unique as they are minimally processed native whey products and retain naturally occurring Cysteine in its original form.

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.

Regarding Whey Protein Concentrate: The Journal Immunology 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.” Fidelus RK, Tsan MF. GSH and lymphocyte activation: a function of aging and autoimmune disease. Immunology 61: 503-508, 1987

* Native: of or relating to the naturally occurring conformation of a macromolecule, such as a protein. Constituting the original substance or source b: found in nature especially in an unadulterated formnative protein to a denatured protein>

* Native Protein: The concept of a protein in its natural state, in the cell, unaltered by heat, chemicals, enzyme action, or the exigencies(distress) of extraction.

**Denature: To cause the tertiary structure of (a protein) to unfold, as with heat, alkali, or acid, so that some of its original properties, especially its biological activity, are diminished or eliminated. It is not possible for a protein to be undenatured.

*** Analysis of protein as determined by an independent laboratory using the SDS PAGE Gel method. This is the industry accepted method to determine the actual biological activity of a milk protein.


Bovine Serum Albumin, alpha-lactalbumin and beta-lactoglobulins

Bovine serum albumin enhances pregastric lipases, promoting more efficient newborn digestion, and it also binds fatty acids in the body. More importantly, it also contains an appreciable amount of cysteine, which is the molecular precursor to glutathione.

Alpha
-lactalbumin is the subunit of lactose synthesis the enzyme which catalyzes the addition of galactose to glucose to create lactose*. It is possible this may aid in infant digestion of milk. It also contains cysteine, though not in as great a ratio as bovine serum albumin.

Beta
-lactoglobulin is involved with the transfer of passive immunity and the binding of retinol and fatty acids. This binding allows for the efficient uptake of fats by the cells.

The presence of
beta-lactoglobulin and alpha-lactalbumin protein in milk is a major cause for allergic reaction in humans. Subsequently, those with true milk allergies to milk protein should not ingest these milk proteins and should caution their use in any form. Lactose intolerance is not a factor in this allergic response. Typically lactose intolerance presents itself as diarrhea from the excess consumption of lactose (this can vary from individual to individual). ImmunoPro® contains low levels (0.3g per 5g serving) of lactose and this is well below the tolerance level for most people.
 

Glutathione

Glutathione (GSH)
Our Body's Master Antioxidant and Best Kept Secret
Glutathione is the body's own natural antioxidant. Antioxidants neutralize free radical activity in the body, and are vitally important for the function of a healthy immune system.

GSH is depleted by oxidative stress, which usually occurs by illness, infection, trauma, medication or surgery.

"Antioxidants are well documented to play vital roles in health maintenance and disease prevention. GSH is our cell's own major antioxidant. Why not use what is natural?"
(1)

Glutathione (GSH) is a tripeptide composed of the amino acids Cysteine, Glutamine, and Glycine. These molecules are found in a larger ratio in non-denatured whey protein compared with any other proteins ingested by humans. Both Cysteine and Glutamine are principle players in the coordinated T-cell response of macrophages and lymphocytes(2).


GSH is naturally found in all the cells of mammals. It provides the principal intracellular defense against oxidative stresses. GSH levels decrease with an insufficient nutrient intake, non-denatured protein specifically. Cysteine in the combined molecule of Glutamine and Cysteine (glutamylcysteine dipeptidesU) is the rate limiting step for GSH production. The natural conformation of the proteins is essential for producing intracellular Glutathione. Therefore the consumption of proteins that are low in Cysteine limit GSH production and availability.


True non-denatured Whey Protein Concentrate
is the optimal nature prescribed precursor (required for the production) of Glutathione (GSH). It contains exceptionally high amounts of non-denatured Cysteine and Glutamine, the amino acids required for intracellular GSH production. It naturally contains the full range of proteins that enhance immune function including the protein bound fats that, in whey protein isolates, have been removed.

There are many whey proteins to choose from. The critical factors are: How was the whey produced? Is it a by-product or a Primary Product? What are the actual amounts of the important proteins measured by independent lab analysis? These questions are addressed in our FAQ Page.

For more research details see
Whey Protein Report, Glutathione by: David Marshall Jr.,O.D., Ph.D.

Glutathione "....since it is this protein more than any other that has been thought to provide a protective function for a number of organ systems, including the crystalline lens of the eye, the retina, prostate gland, and the immune system."(3)

Non-denatured Whey Protein is acknowledged by the medical establishment as a dietary supplement that supports immune function and detoxification. It is now listed in the Physicians Desk Reference (PDR).


Glutathione Benefits

Immune System
Immune Depressed individuals have lower GSH levels when fighting disease. Lymphocytes, cells vital for your immune response, depend on GSH for their proper function and replication.
Immunology 61: 503-508 1987. Cellular depletion of Glutathione has been implicated as a causative, or contributory factor in many pathologies including Parkinson's, Alzheimer's, cataracts, arteriosclerosis, cystic fibrosis, malnutrition, aging, AIDS and cancer (Bounous et al., 1991). In addition, Glutathione is essential in supporting the immune system, including natural killer cells (Droege et al., 1997) and in the maintenance of T-lymphocytes (Gutman, 1998).

Cancer
GSH plays a role in eliminating many carcinogens as well as maintaining immune function towards providing stronger anti-tumor defenses.
Cancer Letters 57: 91-94 1991

Aging Process
It is known that as we age, there is a precipitous drop in GSH levels. Lower Glutathione levels are implicated in many diseases associated with aging, including Cataracts, Alzheimer's disease, Parkinson's, arteriosclerosis and others. Journal of Clinical Epidemiology 47: 1021-28 1994

Athletes
Strong muscular activity generates oxyradicals leading to muscle fatigue and poorer performance. GSH neutralizes these radicals. Whey proteins promote muscular development. Sports Medicine 21; 213 - 238, 1996. Recent research indicates that propensities toward many degenerative diseases and aging itself are related to the capacity of the cell to robustly recover from oxidative insult. The capacity of a cell to recover from such insult can be determined by measuring the intracellular stores of Glutathione. (Noelle et al., 1981)

Antioxidant Functions
Antioxidants are well documented to play vital roles in health maintenance and disease prevention. GSH is our cell's own major antioxidant. Why not use what is natural?
Biochemical Pharmacology 47:2113-2123 1994

Neurological Disease
Low GSH has been demonstrated in neurodegenerative diseases such as MS (Multiple Sclerosis), ALS (Lou Gehrig's Disease), Alzheimer's, and Parkinson's, among others. The Lancel 344: 796-798 1994

Toxins, Pollution, Radiation
GSH detoxifies many pollutants, carcinogens and poisons, including many in fuel exhaust and cigarette smoke. It retards damage from radiation such as seen with loss of the ozone.
Annual Review of Biochemistry 52 : 711-780 1983. The liver is the main detoxification organ of the body. In the liver we find very high concentrations of GSH, as it is a major factor in numerous biochemical detoxification pathways. Numerous studies have demonstrated that patients with compromised liver function due to alcohol abuse have significant reduction of GSH in the liver. (Lamestro, 1995)

AIDS
Low Glutathione levels with poor survival in AIDS patients. Much literature has been written demonstrating the role of enhancing GSH levels in AIDS.
Proc. National Acad. Science USA 94: 2967-72 1997

1. Biochemical Pharmacology 47:2113-2123 1994
2. Droege W, Holm E. Role of cysteine and glutathione HIV-wasting and other diseases associated with muscle wasting and immunoglobulin function. FASEB J 1997; 11:10771089
3. WHEY PROTEIN REPORT,Current Concepts on Whey Protein Usage, Prepared for The Cleveland Eye Clinic,by: David Marshall, Jr., O.D., Ph.D., Consult



Whey Protein Side Effects

Whey protein is considered a very safe supplement for most people when used appropriately. You will want to check with your doctor if you are currently taking any medications to make sure there will not be any adverse reactions with the whey protein. Whey protein side-effects would most likely be caused if you have a true milk allergy (not lactose intolerance), in which case you should avoid any product containing milk. Our Proserum® contains 1g of lactose per 10g serving (which is considered below intolerance levels), and less than 1 percent non-denatured casein.



Whey Protein Quality As Compared to Other Available Proteins

The quality of dietary proteins is a vital factor in determining what proteins are the most valuable in terms of how the body assimilates and utilizes the protein as a resource.

To test these ratios in a protein source we begin with an amino acid analysis, a nitrogen analysis, and then we proceed to the biologic testing. Measuring changes in the protein of the body is a well accepted evaluative analysis used to determine protein quality, measured as Biologic Value (BV). This involves the measurement of nitrogen intake from the protein and the output of nitrogen in the feces and urine. BV is therefore a measurement of the nitrogen absorbed and utilized by the body.

Biologic Value (BV) of Dietary Proteins(1)

Protein

Biologic Value
Whey protein 104
Egg 100
Cow's Milk 91
Beef 80
Fish 79
Casein 77
Soy 74
Potato 71
Rice 59
Wheat 54
Beans 49

As this table shows, the animal proteins are high in BV, and are therefore complete proteins(2). While vegetable proteins are much more incomplete and retain a lower BV rating, due as well to their lower digestibility(1). With a mixture of these vegetable proteins the effect of a complete protein can be produced when eaten in sufficient quantity, but this requires a great deal more total protein to satisfy these requirements.

Whey Protein Concentrates
The benefits (as shown above) of using a whey protein concentrate (WPC) is great according to the BV of this protein source. It fulfills the body's amino acid intake beyond any other source of protein listed above, as well as being a very versatile dietary food. Our Proserum® native whey protein concentrate contains all of the essential amino acids for the body as well as providing cysteine and glutamine. These amino acids are precursors and are necessary for the production of glutathione, a vital free radical neutralizer in the body.

WPC is defined as a whey protein concentrate containing approximately 80% protein. Proserum® is a WPC.

1. Renner E. Milk Protein. In: Milk and Dairy Products in Human Nutrition. Munich: Volkswirtschaftlicher Verlag, 1983
2. Mahan LK, Escott-Stump S. Proteins. In: Krauses Food Nutrition and Diet Therapy, 9th edition, Philidelphia: WB Saunders; 1996


What is Whey? a report by: David Marshall, Jr., O.D., Ph.D.

WHEY PROTEIN REPORT

Current Concepts on Whey Protein Usage, Prepared for The Cleveland Eye Clinic
by: David Marshall, Jr., O.D., Ph.D., Consult

Contents:

INTRODUCTION

A. What is WHEY?

Whey is a by-product of cheese manufacture resulting from drainage of liquid from the curd(1). It contains lactose, protein, ash, and lipids. The protein concentration at this stage of processing is about 67 protein. Whey proteins can be fractioned and concentrated via a process called micro-filtration to yield whey protein concentrates (WPC). The protein concentration can be as high as ~ 95% protein after the removal of the fats and lactose. WPC's are an excellent source of nutrition and are high in lactalbumin, minerals, and vitamins. It possesses a number of functional advantages such as solubility, high water retention, foaming and gelation(1). As a result of these qualities, whey protein concentrates (WPC) have been used in a wide range of food products such as the formulation of dairy foods, egg white replacement, beverages, surimi and comminuted meat products (1).

In response to the efficacy of whey consumption, Karen Collins, M.S., R.D., a registered dietician from the American Institute for Cancer Research, states that whey is a safe and healthy ingredient in foods since levels of pesticides and hormones are not concentrated in whey (2).

Whey protein concentrates are of particular interest to the practitioner due to their wide-range and near full-blend of essential and non-essential amino acids, which are commonly referred to as the building blocks of life. Linked amino acids combine to form proteins. These protein comprise nearly every tissue and organ in the body, therefore any supplementation of the diet with proteins may be beneficial to injury repair, metabolism, and general health.

B. Whey Manufacturing

The importance of whey products has gained prominence within the last 5 years. Asia is the leading exporter of whey produce, exporting an estimated 15,680,683 kg in 1992 and 16,184,519 kg in 1995. This represents~ 60% of all worldwide exports. The leading importer of whey is North America, which in 1995 brought in an estimated 26,444.593 kg . This amount represents a 5 fold increase in imported product over a four year span and nearly 90% of all worldwide imports of whey(3).

Commonly whey is prepared from cheese products such as cheddar cheese. In accordance with the Ohio State University method(11), whey is prepared from milk using lactic acid culture and rennet as a coagulant. The milk is HTST (High Temperature Short Time) pasteurized (163° F, 30 seconds) and held overnight at 40°C then warmed to 30° C and inoculated with 1.5% cheese starter. After incubation for 30 minutes, 38.7 ml rennet extract is diluted with cold water and added to 50 gallons of milk with stirring. Twenty-five minutes later curd is cut and cooked by gradual warming to 38-40°. Cover a thirty minute time interval while the temperature is maintained for 1.5 hours. The whey is then drained through a stainless steel screen and separated at 55° C.

Whey Protein is produced by ultrafiltration at 45° C after addition of 20 g of citric acid with the pH adjusted to 3. After ultrafiltration to 1/5 the original volume, the retentate is diafiltered with addition of 20 g citric acid at pH 3. The concentrated whey is warmed to 40°C and spray dried to, provide whey protein concentrates. This WPC (protein 79.9% and calcium 0.136%) is then used to prepare laboratory scale samples and the WPC solutions are freeze dried(3). Additional micro-filtration techniques may be added to increase the protein yield to ~95%.

Many whey products are then put through an ion-exchange process to remove fat and lactose. In this procedure the cold-filtered protein concentrate is put through a static electrical charge which separates undesirable fractions from the WPC. However, there is a price to pay for this process. The immunoglobulin fraction is greatly reduced(4). The end product is a whey protein isolate that is relatively fat, lactose, and sugar-free product possessing a high amino acid (protein) concentration.

In addition to the before-mentioned procedures, some manufacturers hydrolyze their WPC to produce di-, tri-, oligo-, and polypeptide (long and short-chain amino acids). It also provides for a variety of amino acids, with special emphasis on the branched-chained amino acids (L-leucine, L-isoleucine, and L-valine), in addition to important amino acids such as L-cystine and glutamine, all of which are essential for wound healing, immunity, and cellular nitrogen retention.

note: Hydrolyzing breaks apart peptide bonds. The ion-exchange and hydrolyzing process used on whey protein permanently modifies the native structure. The protein is denatured and the biological activity is ended.

Current Concepts of Whey Usage

A. Nutritional Value

The real nutritional value of WPC's lies in their abundance of amino acids. For example the typical WPC contains up to 18 amino acids, which nearly represents the full blend(57).

Alanine, arginine, and aspartic acid are three common amino acids found in numerous whey proteins. Alanine aid in the metabolism of glucose, whereas arginine causes retardation of tumors and assists in the release of growth hormones and the maintenance of a healthy immune system. It also provides an environment for an increase in muscle mass and body fat reduction, in addition to being an essential ingredient of protein synthesis.

Aspartic acid increases stamina, therefore it is good for fatigue. It also aids in RNA/DNA synthesis.

Cysteine/cystine are perhaps two of the more important amino acids found in WPC. They are helpful in detoxifying toxins and are precursors to the body's most potent antioxidant, glutathione. They promote the burning of fat and are useful in the treatment of rheumatoid arthritis and bronchitis. Due to the possible toxic effects of cysteine at high levels it is not a recommended supplement.

Glutamic acid and glutamine are essential to nervous tissue function. Glutamic acid is a neurotransmitter for retinal neurons and is commonly referred to as "brain fuel" since the brain converts it to a compound that regulates brain cell activity. It is also a precursor to glutathione. Glutamine is important to cellular nitrogen retention and is important in alcoholism, mental ability, impotence and maintaining a healthy digestive tract.

Glutathione, a potent antioxidant, is important for the safe metabolism of the hydrogen peroxide free radical. It helps protect against radiation and oxidative damage and is the body's best defense against the formation of cataracts, age-related macular degeneration (ARMD), cancer, and immunity. This important protein will be discussed in detail later in text.

The essential amino acids are well represented in most WPC's. They can't be manufactured by the body and therefore must be obtained through dietary consumption. They consist of the branched-chained amino acids, lysine, phenylalanine, methionine, and tryptophan. The three branched-chained amino acids are leucine, isoleucine, and valine. They are essential to tissue growth and repair, and promote the healing of bones, skin, and muscle. They also regulate blood sugar levels, so they must be taken in a balance to insure proper regulation.

Phenylalanine is often used to treat depression. It is a precursor to the neurotransmitter, norepinephrine and aids in memory. It should be avoided by phenylketonurics (PKU)

Lysine, methionine and tryptophan are also found in many WPC's. Lysine is an essential building block for all protein and helps to maintain proper nitrogen balance.

The body uses methionine to derive the brain food, choline. It also aids in digestion, as well as serving as a fat burner. It can interact with other substances to detoxify harmful agents, and is essential for the production of cysteine and taurine.

L-Tryptophan acts as a sleep aid, as demonstrated by the drowsy feeling we sometimes experience after Thanksgiving dinner (turkey meat has a relatively high amount of tryptophan.). It is also necessary for the production of niacin and is used by the body to make the neurotransmitter, serotonin.

The rational for using WPC's to attain this dietary level of nutrition is that 25 grams of powder provides approximately 20 grams of amino acids. To achieve this level of nutrition taking tablets or soft gels would require taking 48 to 60 units per day, which would be difficult and expensive.

B. Body-building

A large number of weightlifters and bodybuilders use WPC's during their training regimen. They sometimes utilize a three step process which consists of stacking, "cycling", and "cutting". The initial stage, stacking involves taking two or more compounds at one time to maximize results. They may take WPC and or creatine or chromium. This is then followed by cycling, in which large doses of a supplement is used to change the level of body fat. Some will use 10 or more one ounce WPC servings a day. This should be approached with caution since large doses of protein consumption may present challenges to the liver. The final stage, cutting, involves maximizing the muscle bundles for visualization. This is the point in which the bodybuilder aspires to achieve that "cut up" appearance.

It is important to consult a physician before attempting any of these extreme methods.

C. Clinical Implications

1. Wound Healing

Australian researchers claim that whey extract could become a standard treatment for chronic wounds, especially ulcerations from diabetes and hypertension. Initial experiments using a whey extract containing a number of natural growth factors excelled at spurring cells to grow thus prompting this essential step in the body's normal repair of injuries(32). The compound also encouraged rapid wound healing in rats and pigs(32).

Scientists working on a joint government-industry project at the Cooperative Research Center for Tissue Growth and Repair in Adelaide, Australia have patented a process for mitogenic bovine whey extract which is unique as a naturally-derived cocktail of growth factors in which 1000 L of milk yields 30 grams of extract. When the extract is mixed with a collagen gel and applied to wounds it enhanced the healing of surgical incisions.

These observations have their origin in the fact that whey protein contains high levels of amino acids which may be important to wound healing. These amino acid include arginine, glycine, and particularly the branch-chained amino acids (BCAA) leucine, isoleucine and valine, which are essential to promote healing of bones, skin, and muscle tissues. Another amio acid, proline, aids in the production of collagen, heals cartilage and strengthens joints, tendons and cardiac muscle.

2. Glutathione

In order to understand the mechanisms beneficial biochemical interactions and possible whey protein potential health benefits of WPC, a brief biochemical review of the protein Glutathione is required, since it is this protein more than any other that has been thought to provide a protective function for a number of organ systems, including the crystalline lens of the eye, the retina, prostate gland, and the immune system.

a. Glutathione Synthesis

For the body to produce Glutathione (GSH) six building blocks are required: L-glutamate, L-cysteine, L-glycine, magnesium, potassium, and 5' ATP. Two enzymes are also required and they are L-gamma-glutamyl-cysteine synthetase (equation 1) and glutathione synthetase (equation 2) and the reaction proceeds in the following manner:

Mg 2+

(1) L-glutamate + L-cysteine + ATP--------->

L-gamma -glutamylcysteine + ADP + P

Mg2+

(2) L-gamma-glutamylcysteine + L-glycine +ATP----------->

K+

L-gamma-glutamylcysteinylglycine +ADP + P

L-cysteine is the rate limiting substrate in this reaction12 , while the rate controlling enzyme for the reaction is L-gamma -glutamylcysteine synthetase(5) .

b. Scavenger Pathways

The 2 major functions of glutathione are to detoxify hydrogen peroxide (H2O2) and other organoperoxidases (free radicals) and to defend against oxidation within cells via the Glutathione Redux Cycle, or more commonly referred to as the Scavenger Pathways(6,7).

Glutathione plays it's role of "scavenger" through out the body. The role of scavenger is primarily accomplished through glutathione peroxidase (GSH px). The peroxidase interacts with the H2O(2) to reduce it to harmless water, thus limiting it electron stealing capacity. This is illustrated in the following equation:

(2) 2-glutathione-SH +ROOH ------>

glutathione disulfide + ROH + H2O

The disulfide is then reduced with the co-enzyme NADPH in the prescene of the enzyme Glutathione Reductase to yield the original glutathione compound.

(3) glutathione reductase +NADPH + H+ ----------->

2-glutathione-SH + NADP -

Many theories of aging and disease are based upon the interaction of the formation of free-radicals and the subsequent reduction in glutathione levels which allows for an accumulation of free-radicals to remain within a cell and organ or organ system. Free-radicals that remain within cells may cause cell damage, DNA damage and may even cause cell death, cancer transformation or loss of cell immunity to viral or bacterial infection.

3. Ocular Ramifications

To fully appreciate the manner in which supplementation with WPC may be beneficial to maintenance of ocular tissues, let us look at the processes of cataractogenesis and oxidative insult to the retina.

a. Cataracts

1. Mechanisms of cataractogenesis

The exact mechanism of cataract formation follows a strict ordered sequence. Initially, in the pre-cataractous state, a cascade of early cataract-related changes occurs resulting in an oxidative insult to the cell membrane and to the amino acids methionine and cysteine (17-20). This can be caused by x-rays, photochemical insult, hyperbaric oxygen levels 18 and other causes. The remaining cascade of events then proceeds in the following manner: (a) unfolding of protein structures, which exposes the protein thiols making them available for further oxidation, (b) di-sulphide linked aggregate formation, and (c) a decrease in enzymatic activity (glutathione peroxidase) which protects and repairs damage (17,18,20). It is at this stage that the cataract truly begins to develop accompanied by a change in the lens Redux ratio, decreased ATP levels, and a change in cation permeability which induces an influx of H2O (water) within the cell membrane(17-20).

The site of initial damage according to Spector(18) occurs in the lens epithelium. The causative agent at this point is thought to be primarily the hydrogen peroxide radical, which in the absence of glutathione, may now accumulate unopposed. These free-radicals which are defined as molecules with an one or more unpaired electrons in their outer orbit, which attempt to stabilize their charge by stealing an electron from the outer shell of a stable neighboring molecule setting off a chain-reaction sequence(6), causes DNA damage to the lens epithelium cells(21). Examination of lens epithelial cells at the time of cataract surgery usually reveals an ongoing pattern of programmed cell death (apoptosis)(18) which may be documented by evaluation of lens chromatin fragmentation(21) .

In the case of experimentally UV-induced cataracts, exposure to the UV radiation generated hydrogen peroxide, superoxide and DNA damage(21,31). The consequences of this action is to degrade the lens crystalline, decrease transmembrane voltage, reduce glutathione stores(24), decrease enzyme activity, and increase in prostaglandin production(25). It is interesting to note that no significant change in the non-protein thiols occurred until 85% of the lens epithelium cells were already dead(21).

2. Cataractogenesis and Glutathione

The major role of glutathione in the crystalline lens of the eye is to provide lens clarity via maintenance of the limiting anterior epithelial cell layer and to correct and/or halt oxidative damage to the lens(5). Arnold was perhaps the first investigator to discover the presence of glutathione in the lens, and it is now clearly evident that the highest concentration of glutathione is found in the lens epithelium(6) , which has a 5X greater concentration than in the second most glutathione rich site, the lens cortex. The nuclear region of the lens is primarily devoid of GSH(5,6).

It is well is established that lenticular glutathione levels decrease with age (5,6,8) ranging from a concentration of 3.5 umol/g at age 20 and decreasing to 1.8 umol/g at age 65. It is inferred that it is this age related reduction in GSH which is in part responsible for cataract formation in the elderly. In fact, Reis was the first to note the lack of GSH in cataractous lenses(5). In addition, a number of substances which inhibit GSH synthesis, such as Buthionine Sulfoximine(16) produce cataracts in experimental conditions. It is interesting to note that glutathione levels are unchanged in some reversible forms of cataracts, such as those induced after the administration of diquat(5). Reduced GSH levels is a precipitating factor age-related cataract formation(7). To further illustrate this point, researchers at Alcon Laboratories have used aldose reductase inhibitors to halt the progression of certain cataracts(13). The importance in this finding is that aldose reductase acts competitively to reduce levels of GSH and its inhibition allowed GSH levels to remain high.

As mentioned previously, glutathione and it's enzyme, glutathione peroxidase has great importance in regards to the elimination of free-radicals within the lens. Recent reports indicate that glutathione metabolizes chronic low levels of free-radical production26 typical of normal metabolism and the most potent anti-oxidant in the lens system. This point is illustrated by the inability of other enzymes, such as catalase to limit lens damage caused by hyperbaric oxygen(27) and H202(28,29).

Glutathione is essential for the maintenance of tissue ascorbate (Vitamin C) and alpha-tocopherol (vitamin E) levels (30) according to Mrtensson. He found that as GSH levels decreased, a corresponding decrease in ascorbic acid and vitamin E followed, which led to systematic mitochondrial death, which in turn leads to a cessation of cellular metabolism(31).

The regional distribution of glutathione in different cataracts is of interest. Pau (et al 9) found that in primary nuclear and supranuclear cataracts, there was only a slight decrease in GSH levels relative to the subcapsular and (20) nuclear, implying a different mechanism for various cataract types and possibly a different mode of non-surgical intervention.

Experimental data has shown that supplying the lens with additional glutathione, particularly in the form of the peroxidase increases delays cataract development and may even prevent cataract development(23). This may be accomplished my enriching the aqueous with the glutathione precursor amino acids or glutathione directly(10) . Glutathione in conjunction with vitamin E added as a supplement to a galactose diet did halt opacification of cortical cataracts in the animal model15. Further evidence for GSH infiltration into the lens comes from the identification of glutathione transporters in the lens epithelium(11). Taking glutathione orally has not been shown to raise tissue levels of glutathione. Taking WPC which contains high levels of cystine, the rate-limiting substitute for the production of glutathione, may be helpful for the prevention of cataracts.

b. Macular degeneration

It is widely accepted that lipid peroxidation plays a major role in retinal light damage(58). The vertebrae retina is known to contain relatively high levels of antioxidants and anti-oxidant enzymes(59). Among these are three members of the glutathione system, glutathione peroxidase, reductase, and transferase. The others are catalase and superoxide dismutase (60). When levels of these antioxidants begin to decrease with increasing age(59, 60) , retinal changes associated with macular degeneration begin to develop. This is particularly true for glutathione peroxidase and catalase(59, 60) .

The method oxidative damage occurs is due to light or heat damage and then coupled with the age-related reduction in GSH(px) and catalase allows for the propagation and accumulation of the free radicals, making the retina susceptible to further damage(60).

Stone and Dratz (61) found evidence of glutathione-dependent enzymes in the outer segments of rats and suggest that since these membranes are rich in polyunsaturated fatty acids, they are susceptible to free-radical induced peroxidation. Therefore when RPE disruption occurs with early ARMD, which limits the amount of phagocytosis occurring, coupled with the age-related reductions in antioxidant activity, adverse retinal changes are manifested and may proceed unchallenged.

It may therefore be possible to replenish or revitalize the antioxidant activity of the retina by dietary supplementation primarily with a glutathione or precursor to halt the progressive lipid peroxidation occurring during ARMD.

c. Immunity

Primarily the process of enhancing the immune response is accomplished through the replenishment of glutathione (GSH). It has been theorized that the ability of lymphocytes (CD4 cells) to correct oxidative damage is determined by their capacity to regenerate intracellular stores glutathione which allows them to respond vigorously to a wide variety of antigens(33).

In 1981, researchers discovered that mice fed a non-denatured whey protein concentrate exhibited a marked increase in antibody production in response to T-cell dependent antigens(36). Numerous experiments in subsequent years have confirmed this early observation (37,38,39,40,41,42,43,44). Thus, enhanced immunity against colds and hepatitis and most dramatically pneumococcal infection(42) could be accomplished through dietary supplementation with whey protein concentrates (WPC's).

An interesting peripheral observation was that the immuno sustaining effect of the protein mixture found in whey was unrelated to its nutritional efficiency and as a result of this phenomenon this unique property was defined as the bioactivity of the product(33).

This 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 GSH or GSH 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(33).

The proposed bioactivity is dependent upon three bioactive proteins contained in whey, serum albumin, lactoferrin and alpha lactalbumin. These proteins contain a high number of cysteine/cystine residues, an important GSH precursor. Serum albumin contains 17 cysteine/cystine residues/ 66,000 MW molecule and 6 glutamylcysteine dipeptides(39). Lactoferrin contains 17 cysteine/cystine residues/ 77,000 MW molecule and four gluatmylcysteine dipeptides, while alpha-lactalbumin contains 4 residues per 14,000 Mw molecules (39). It is these residues which are primarily responsible for replenishment of GSH stores.

d. Cancer

Two major theories of oncology both implicate GSH as a putative protective factor due to its dual role as a antioxidant and detoxifying agent. Free radical accumulation is thought to be a major factor in tumor formation (45). In fact at least twelve carcinogens have been identified that are detoxified by GSH conjugation. These are: aflaxotoxin B1, N-acetyl-2-aminofluorene, benzanthracene, benzopyrene, benzidine, dimethyl-hydrazine, 1-nitropyrine dimethylnitrosamine, ethylmethane sulfonate, N-methyl-4-aminobenzene, 7-methylbenzanthracene and 3-methyl-cholanthracene (46,47,48).

Further evidence supporting the anti-tumor forming capacity of whey protein is illustrated by a University of Wisconsin study in which hormones known as androgens are responsible for depleting GSH levels in the prostate. This relatively GSH-free environment is thought to promote prostate carcino-genesis in men (49). This condition can be reversed in vitro by increasing colonial levels of GSH via continuous whey protein supplementation.

e. Diseases of Aging

As in carcinogenesis, free-radical accumulation has been implicated in producing a variety of diseases associated with aging (50).These maladies result from the toxic accumulation of these materials due to the absence or reduced levels of GSH. Diseases such as Alzheimer's (51), Parkinson's 52, and arteriosclerosis53 all appear to be preceded or associated with cellular organ or organ system reductions in GSH. Therefore much speculation has arisen regarding the potential benefits supplementation with whey protein may provide in these cases. If results obtained from other organ system studies are of any indication results could be promising.

f. HIV and AIDS

The mechanism by which whey protein concentrate yields an enhanced immune response has already been discussed. Recently this knowledge has been applied to the treatment of HIV infected individuals. Staal (et al 34) reported that HIV-infected individuals have lower GSH concentrations in their blood lymphocytes, while Herzenberg (et al 35) found that the more glutathione patients carry in their CD4 helper T-cells, the cells primarily targeted by the HIV virus, the greater the chance of increased longevity exists.

More recent claims have stated that supplementation with whey protein concentrates (WPC's) may help AIDS patients maintain body weight and in some cases limit wasting syndrome. In a pilot study WPC's were given to a population consisting of 14 AIDS infected children (ages 8 months-15 years) in an attempt to limit determine the efficacy of daily oral dietary ingestion of whey proteins. They found no toxic side effects and an average weight gain of 3.2 - 18% from their entrance weight(54).

A. Robert Neurath M.D. and his colleagues at the Laboratory of Biochemical Urology at Lindsley F. Kimball Research Institute of the New York Blood Centers has reported that a modified version of protein extracted from whey blocked the aids virus from infecting cells in vitro(55). In their National Institutes of Health sponsored study the scientists modified beta- lactoglobulin to produce a substance referred to as B69. They reported that B69 latched onto a protein structure called CD4 on the surface of cells which kept the aids virus from using this site as an entryway into the cell.

Newarth further hypothesized that if additional results with B69 were promising, the compound may be formulated into a cream or foam that could be dispensed within condoms to limit the transmission of the virus.

Dr. Jefferey Laurance, an AIDS researcher at Cornell Medical College, however, urges caution regarding B69 developments. He states that HIV can infect some cells , including rectal and vaginal cells, without using the CD4 site as an entryway.

In summary, animal studies have yielded promising reports regarding prolonged life spans of infected animals in the laboratory, while theoretical data(56) and initial clinical observations in humans have produced evidence that dietary supplementation with WPC's can provide definite benefits to the HIV infected individual. Further research, however, is warranted in this area.

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Collins, K.. Is Whey Good for You? How do Cooking Oils Differ? Medical Tribune News Service, 1997.
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Exports and Imports of Whey products. Statistics, Canada, Dairy Section, AAFC, 1997.
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1 Nutrition, Frequently Asked Questions.AST Research Communique, 1997.
5
Rathburn, WB. Glutathione in Ocular Tissues. 469-510.
6