© Whole Foods Magazine

December 2006




An Interview with ATP Pioneer Dr. Eliezer Rapaport The Science of ATP: Part 3


By Richard A. Passwater, Ph.D.


We have been chatting with adenosine triphosphate (ATP) research pioneer Dr. Eli Rapaport for the past two months by discussing the basic chemistry of ATP and Dr. Rapaport’s research that has led to important health findings for ATP supplements.

We have discussed how ATP is used within cells (intracellular) to produce and store the energy that drives the countless thousands of biochemical reactions that produce “life.” The energy contained within the chemical bonds of ATP is converted to both chemical and mechanical energies. ATP’s high energy bond can be transferred to other compounds to drive the biochemical reactions that move nutrients into cells, remove waste products, propel nerve signals, make proteins and other body compounds, move skeletal muscles, contract the heart muscle and virtually everything that involves life.

What we have learned from Dr. Rapaport’s research is that ATP also has extremely important roles outside of cells (extracellular) as well. Extracellularly, ATP and its in vivo degradation product, adenosine, activate specific ATP and adenosine receptors on cells such as in the artery linings, nerve endings and various organs to produce beneficial health effects. As a result, extracellular ATP and adenosine are regulators of many physiological responses including vascular, heart and skeletal muscle functions. Oral ATP supplements directly increase extracellular blood plasma ATP pools to improve blood vessel tone, increase vasodilation and enhance blood flow. Not only is extracellular ATP cardioprotective and organ protective, it enhances delivery of nutrients and oxygen to the brain, heart and all tissues and organs of the body as well as stimulates removal of waste products such as lactic acid. Furthermore, extracellular ATP can increase needed intracellular ATP as it is used up; it accomplishes this by stimulating oxygen and glucose disposal that are needed for intracellular ATP synthesis.

Let’s resume our chat with Dr. Rapaport about his research. As you may remember, Dr. Rapaport received his Ph.D. from Johns Hopkins University in 1971. He serves on the faculties of Harvard Medical School at the Massachusetts General Hospital, Boston University School of Medicine and the Worcester Foundation for Experimental Biology.


Passwater: When you first developed ATP supplements, were you attempting to directly raise intracellular ATP?


Rapaport: No, I understood that intracellular levels of ATP are too high to be affected directly. The total amount of ATP in liver is 3 millimolar or about 3.7 grams and the total amount of ATP in blood is 0.9 millimolar or 2.3 grams, considering a blood volume of 5.5 liters in an adult. These types of ATP levels could not be affected by acute administration of oral ATP.

However, I discovered that blood plasma levels of ATP were in the submicromolar range totaling less than 1 mg. These levels could definitely be elevated by the acute administration of oral ATP, and later I found out that they easily were.

I also knew however, that mitochondrial ATP synthesis was strictly dependent on oxygen and that oxygen could be metabolically expensive since its availability is dependent on blood flow. Glycolysis, which proceeds anaerobically does not require oxygen presence but is dependent on glucose or its storage form, glycogen. In addition, I knew that contracting skeletal muscle releases ATP and adenosine and that the release of ATP and adenosine by the exercising muscle is a biological mechanism for answering the metabolic demands of the ATP-depleted muscle.

Thus, it became clear that extracellular (blood plasma) ATP, which is the master regulator of blood flow and acts in very low levels, can achieve enhancement of cellular ATP synthesis by stimulating the intracellular pathways of ATP synthesis.

When I found that blood plasma pools of ATP are extremely low, one ten thousandth the pool of red blood cell, and can be easily increased by administration of ATP in animals, I began studying the route of ATP from the point of its administration to its appearance in the blood plasma. I used radioactively double-labeled ATP, labeled by radioactive phosphates as well as tritium on the adenine ring. The mechanisms that yield increases in blood plasma ATP pools were established by following the radioactive labels.

As previously mentioned, it was found that oral ATP, which has a first passage liver effect, can easily increase blood plasma ATP pools. I then demonstrated that the pathway of red blood cell ATP synthesis originates from adenosine, which is supplied to the red blood cell by the turnover of the hepatic ATP pools and that red blood cells release their expanded ATP pools into the blood plasma in a non-hemolytic process. That was the first known example of ATP released from a cell, any cell, into the extracellular environment also termed interstitial fluid in tissues.


Passwater: What led you to observe that your ATP supplements produced health benefits by acting intracellularly or extracellularly?


Rapaport: I was fascinated by the work of Dr. Tom Forrester in the 1970s. He was trying to justify the Roman aphorism “mens sana in corpore sano” or a healthy mind in a healthy body. He was attempting to identify the metabolic communication between exercising muscles and increased oxygen consumption in the brain, which translates into improved brain function. The system he studied dealt with the release of purines, ATP and adenosine from skeletal muscle during exercise, and their effect on the subsequent improvement in blood flow. Since I was interested in cancer and the inverse relationship between exercise and tumor development in experimental animals, which was established, I looked further into this phenomenon.

What I found in the literature was that in exercising rats, experimental tumor volumes were inversely related to the levels of exercise (and therefore to the level of blood plasma ATP). Epidemiological studies in humans also indicated inverse relationship between incidence of cancer and regular exercise. Epidemiological studies showed then and still demonstrate today that regular exercise in humans has a long list of favorable effects. These effects range from maintaining insulin sensitivity and glycemic control to regulating normal blood pressure. Furthermore, it was known that tumor metastases, the spread of secondary tumor growth, in striated muscle were clinically rare.

This sequence of events led me to my early studies of ATP administration into tumor-bearing mice whereby I began to establish the mechanism of extracellular ATP formation from exogenously supplied ATP in general and the effects of ATP infusions in advanced cancer in particular. The early studies in experimental animals showed improvements in a variety of organ functions, especially liver, in tumor-bearing animals.

These studies provided the first indications that increases in liver, blood and blood plasma ATP pools produced survival advantages in tumor-bearing mice and that these survival advantages were directly related to the increases in hepatic ATP pools. Animals with advanced disease died not from the effects of the tumor but from liver failure. Elevated liver ATP pools shifted liver protein synthesis from acute phase protein synthesis to a normal spectrum of liver protein synthesis. It meant increase in albumin synthesis and decreases in C-reactive protein and lactate dehydrogenase (LDH) synthesis as well as decreases in blood liver enzymes.

I also noticed that stressed animals or tumor-bearing animals had lower than normal liver, red blood cell and blood plasma ATP pools. Stress was introduced in mice by shifting the light-dark cycle in the animal room once every few days depending on the desired level of stress.


Passwater: Previously, we have discussed that specific ATP receptors are activated and you described P2X and P2Y ATP receptors, as well as adenosine receptors A. Please review briefly and as non-technically as possible, what an ATP or adenosine receptor is and what it does.


Rapaport: Receptors are proteins that are imbedded in the cell membrane and contain extracellular loops to which the ligand (ATP or adenosine in our case) binds. The receptor contains intracellular loops as well and upon binding of the ligand to the receptor outside the cell, the intracellular loops undergo changes in shape (conformation) that in turn promote changes in cellular function (originating by the binding of the ligand to the receptor outside the cell).

ATP receptors are either P2X, ionotropic receptors, or P2Y metabotropic receptors. Adenosine receptors are A1, A2-alpha, A2-beta and A3, all metabotropic receptors. The ionotropic P2X receptors are non-specific ion channels whereby the binding of extracellular ATP results in inflow of Ca++ and Na+ ions into the cell and outflow of K+ to the outside of the cell. Once this happens, the cell membrane is depolarized and a signal of action potential is fired. The metabotropic P2Y receptors bring about stimulation and /or inhibition of intracellular synthesis of certain signals (produced inside the cell by activation of the enzyme phospholipase C or stimulation or inhibition of the enzyme adenylyl cyclase) upon the binding of extracellular ATP to the receptor outside the cell.

To date, seven different P2X receptors subtypes, eight different P2Y receptors subtypes and four adenosine (A) receptors subtypes have been identified. Once the intracellular signal is delivered, the cell performs a function that is therefore initiated by the binding of ATP or adenosine to the specific receptors outside the cell. These functions are numerous and vary from vasodilation of blood vessels to detection of particular tastes or serving in detection of low blood oxygen levels.


Passwater: Although, oral supplementation of ATP doesn’t directly raise intracellular ATP, isn’t intracellular ATP indirectly increased by oral ATP supplementation, as well as its promoted increases in extracellular ATP?


Rapaport: Absolutely, by enhancing blood flow, extracellular, blood plasma pools of ATP, stimulate the disposal of oxygen and nutrients, mostly glucose, at peripheral sites such as skeletal and cardiac muscle as well as support the removal of waste products such as lactic acid and ammonia. In addition and as importantly, blood plasma pools of ATP stimulate blood flow, oxygen and glucose consumption by the brain.

The importance of this activity is that in the brain improved blood flow equals improved metabolism, which yields benefits to brain functions. By improving blood flow and thus answering cellular metabolic demands, extracellular ATP indirectly enhances cellular ATP synthesis. Adenosine and ATP were also shown to potentiate the insulin-stimulated glucose transport by increasing the levels of GLUT 4, the glucose transporter, on the membrane of skeletal muscle. Cellular ATP synthesis by glycolysis, the breakdown of glucose to three carbon units is the preferred mode of cellular ATP synthesis since it can proceed in the absence of oxygen.


Passwater: This is important new information for a lot of people, including cardiologists and scientists. Can you give me a couple of references for their benefit?


Rapaport: Well, off the top of my head I can quickly give you three key references, but there are more. The article by Susanne Leij-Halfwerk et al. demonstrates that extracellular ATP expands liver ATP pools in humans in a direct manner. (Leij-Halfwerk S., Hendrik J. Agteresch, P. E. Sijens, and Dagnelie P.C. Hepatology 2002;35:421-424)

A second article that comes to mind discusses the significance of stimulating glycolysis in the diseased heart for the purpose of generating “glycolytic” ATP, which also expands indirectly the heart’s ATP pools. (Opie, LH, The Lancet Vol 364 November 13, 2004)

A third paper shows that adenosine stimulates glucose disposal (uptake by GLUT 4) in skeletal muscle and provides the references for the well-established adenosine-induced stimulation of glucose uptake by cardiac muscle as well as in adipose tissue. (Han, D-H; Hansen, P. A.; Nolte, L. A. and Holloszy, J. O. Diabetes 47:1671–1675, 1998) There are many more publications related to the indirect stimulation of ATP synthesis in humans, and I have published animal studies about this myself.


Passwater: How do extracellular ATP and adenosine affect skeletal muscle function by stimulating glucose disposal?


Rapaport: The main glucose transporter is a protein GLUT 4, which is synthesized inside cells and upon the action of insulin at the insulin receptor membrane site, GLUT 4 is translocated to the cell membrane and becomes active in transporting glucose from the blood into the cell. Skeletal muscle is the most important peripheral target (separate from the central target, the brain) for insulin action and glucose uptake. The regulation of skeletal muscle glucose uptake is a primary factor in maintaining proper health since skeletal muscle contains about 80% of the body carbohydrate stores in the form of glycogen.

As discussed previously, glycolysis, the breakdown of glucose from glycogen or from transported glucose, is the preferred mode of intracellular ATP synthesis because it is not dependent on oxygen presence and can proceed under poor blood flow conditions. Such conditions may exist during endurance exercise whereby skeletal muscles are hypoxic (in an oxygen poor environment).

There is increasing data that adenosine is an important regulator of insulin’s actions in skeletal muscle cells. Adenosine was reported to increase the sensitivity of insulin receptors to the action of insulin and thus stimulate disposal of blood glucose into skeletal muscle cells. This activity of adenosine is mediated by the adenosine A1 receptor, which has been linked to insulin signaling by augmenting the activity of insulin at its receptor.

Therefore adenosine, which is the in vivo degradation product of ATP, has a significant role in maintaining and improving insulin sensitivity. Once insulin sensitivity is impaired, insulin resistance gradually develops followed by Type 2 diabetes and its clinical complications.


Passwater: You have been involved in the development of intravenous administration of ATP in the treatment of non-resectable, advanced refractory cancer in patients who have failed surgery, chemo-and/or radiation therapy. Could you review these clinical trials.


Rapaport: Since the 1960s it has been observed that patients suffering from a variety of cancers have lower levels of erythrocyte ATP pools as compared to healthy controls. These findings were in agreement with various studies that have recognized a strong relationship between aging and the development of cancer. The decline in erythrocyte ATP pools was also observed in patients with a variety of other advanced life-threatening diseases.

In the early 1980s I demonstrated in several published studies that the administration of ATP to tumor-bearing animals yielded significant inhibition of tumor growth and in cachectic-weight losing animal tumor models, both inhibition of tumor growth and host weight loss. These two activities of ATP were not interrelated but were in direct relationship to the expansions of liver, red blood cell and blood plasma ATP pools.


Passwater: What is the biological significance of extracellular ATP in the control of tumor development?


Rapaport: Cancer cachexia in humans suffering from advanced cancers is associated with host weight loss, with anorexia, hormonal aberrations and depletion and redistribution of host metabolic factors. It is the decline in vital host functions and organ failure, which leads to subsequent death. In advanced cancer patients, gluconeogenesis, which is the synthesis of glucose from three carbon unit catabolic products such as lactic acid, alanine or glycerol, takes place in the liver at a large energy (ATP) cost. Glucose is then taken up by the tumor and is broken down by glycolysis yielding a much smaller amount of energy. This type of host-tumor interplay and the liver-tumor futile cycle are responsible for the depletion of visceral energy stores, skeletal muscle function and blood ATP pools in patients suffering from advanced cancer.

My studies of the early 1980s demonstrated that the liver has a central role in controlling the progression of cancer in the advanced-disease patient, and, as importantly, intracellular pools of ATP in the hepatic parenchymal cells were the major factor in affecting liver function. When liver ATP pools were low, liver protein synthesis shifted to the synthesis of acute phase proteins leading to inflammation and overall decline in bodily functions. The hallmarks of these activities were low albumin, low pre-albumin, high liver enzyme levels in the blood, high C-reactive protein levels, high tumor necrosis factor-alpha and high lactic acid dehydrogenase (LDH) levels in the blood.

Increasing liver ATP levels to normal or above normal levels by administration of exogenous ATP initiated a reversal in the spectrum of protein synthesis by the liver along with inhibition of gluconeogenesis, thus stopping the drainage of visceral energy stores. Along with the changes promoted by administration of ATP, survival advantages and the slowdown in disease progression became noticeable.


Passwater: What do clinical trials with ATP on cancer patients indicate?


Rapaport: The utilization of continuous intravenous infusions of ATP at levels below 100 mcg/kg of body weight per minute, levels which do not affect heart rate or arterial blood pressure, were shown in four different human clinical trials in the United States and The Netherlands to have a variety of measurable positive effects in advanced cancer patients, mostly patients suffering from non-resectable, advanced, refractory, stage IIIB/IV non-small-cell lung cancer (NSCLC) with life expectancy of about six months.

In a phase II trial and a small phase III trial, which included a control arm of best supportive care without ATP infusion, of stage IIIB/IV NSCLC patients, statistically significant survival advantages compared to best supportive care controls and historical controls were recorded.


Passwater: In advanced cancer, terminal stage disease and death are due to hepatic and multiple organ failure rather then the tumor itself. Quality of life declines rapidly. Did the studies examine this?


Rapaport: Yes, this point that you make is the key to the treatment of advanced, refractory cancer as well as other advanced diseases. In addition to inhibition of progression and stabilization of the disease, a variety of quality of life end points were obtained by the use of validated advanced cancer questionnaires. These included, in particular, improvements in appetite and reduction in fatigue, two of the most problematic aspects of advanced cancers. Improved liver function by ATP infusions affected the synthesis of proteins, which are positive prognostic factors in advanced cancer. Continuous intravenous infusions of ATP improved skeletal muscle strength as measured by several methods in two separate clinical trials.

Finally, Karnofsky performance status, which is determined by the clinical investigator, contrary to the validated questionnaires answered by the patients and which is a surrogate quality of life parameter, was stabilized in patients receiving ATP infusions. The current experimental protocols utilize once-weekly continuous intravenous infusions of ATP for eight hours at levels up to 50 mcg/kg per minute on an outpatient basis either in an outpatient clinic or in home care. This particular protocol is administered in clinical trials involving patients suffering from a variety of non-resectable cancers who have failed surgery, chemo-and/or radiation therapy and who have life expectancy of less than six months.


Passwater: I assume that you used continuous intravenous infusions of ATP because it was easier to elevate ATP levels and easier to control in a clinical trial. Once the research is completed, would you foresee being able to raise extracellular ATP levels sufficiently via oral supplementation to obtain significant results?


Rapaport: You are correct; the utilization of continuous intravenous infusions was designed to achieve controlled elevation of ATP pools in a short period of time. I do foresee the use of oral ATP since we know now that oral ATP formulations can promote elevations of bodily ATP pools.


Passwater: Is reduction in fatigue in advanced cancer patients treated with ATP administration related to improvements observed in measurements of skeletal muscle function, and would these effects apply to other groups?


Rapaport: Attempting to improve skeletal muscle strength has not been limited to patients suffering from advanced disease. The desire to slow the aging process by improving skeletal muscle strength (function) has attracted a considerable degree of interest over time and has been the Holy Grail of aging research. Hormone treatments of elderly men with human growth hormone (GH) and testosterone and hormone treatment of elderly women with GH and hormone replacement therapy (HRT), was the subject of a recent large clinical trial. The results confirmed the apparent positive effects of growth hormone and sex steroid combinations on body composition, namely, increasing lean body mass and decreasing fat mass.

However, the results clearly demonstrated that lean body mass did not translate into improved skeletal muscle function, and, as importantly, the risk of adverse effects especially in the form of Type 2 diabetes associated with the use of these hormonal regimens was substantial. The improvements in hepatic, blood flow and muscle functions that were observed in advanced cancer patients after ATP administration, raise hopes that these parameters can be positively affected by different modes of ATP administration in other populations. The primary independent negative prognostic factors of survival that significantly benefited from ATP administration were serum albumin and serum bilirubin levels, serum lactate dehydrogenase (LDH) levels, blood levels of tumor necrosis factor-alpha (TNF-alpha), skeletal muscle strength and Karnofsky performance status, all of which are also known to be significant quality of life determinants. These prognostic factors however, are not limited to advanced cancer and exist in most if not all advanced diseases as well as in aging itself.


Passwater: We will discuss the individual indications for oral ATP in the next interview, but right now, let’s discuss ATP supplements and what structure/functions claims are allowed for oral ATP?


Rapaport: I will confine my remarks to PEAK ATP , which is a trademarked dietary supplement prepared according to my issued patents and shown to increase circulatory ATP pools in blood plasma (extracellular).

The structure/function claims for PEAK ATP formulations are:

1. Improves vascular health, circulatory functions and blood flow to peripheral sites.

2. Increases overall energy levels and reduces fatigue.

3. Benefits skeletal muscle function, strength, and recovery.

4. Boosts mental acuity and may lessen the perception of fatigue and/or exercise-associated pain.

5. Protects heart and liver functions.

6. Promotes glycemic regulation.

7. Supports joints health.

The structure/function claims for PEAK ATP (oral ATP-disodium formulations) are based on claimed benefits of supplementation, of a classical human metabolite deficiency, with the exact same metabolite.

1. Severe declines (50%) in human physiological ATP pools have been demonstrated in skeletal muscles and red blood cells during aging (Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaaimal S, Nair KS: Decline in skeletal muscle mitochondrial function with aging in humans. Proc. Natl. Acad. Sci. USA 2005; 102:5618-5623. Conley KE, Jubrias SA, Esselman PC: Oxidative capacity and ageing in human muscle. J. Physiol. 2000; 526:203-210. Rabini RA, Petruzzi E, Stafolani R, Tesei M, Fumelli P, Pazzagli M, Mazzanti L: Diabetes mellitus and subjects’ ageing: a study on the ATP content and ATP-related enzyme activities in human erythrocytes. Eur. J. Clin. Invest. 1997; 27:327-332).

Muscle contraction, exercise and physical endurance result in loss of skeletal muscle ATP pools (Steiner MC, Evans R, Deacon SJ, Singh SJ, Patel J, Fox J, Greenhaff PL, Morgan MDL: Adenine nucleotide loss in the skeletal muscles during exercise in chronic obstructive pulmonary disease. Thorax 2005; 60:932-936. Jianhua L, King NC, Sinoway LI: Interstitial ATP and norepinephrine concentrations in active muscle. Circulation 2005; 111:2748-2751).

Adverse physical conditions resulting from physiological stress or disease produce significant losses in muscle, blood and organ ATP pools (Weiss RG, Gerstenblith G, Bottomley PA: ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc. Natl. Acad. Sci. USA 2005; 102:808-813. Park JH, Phothimat P, Oates CT, Hernaz-Schulman M, Olsen NJ: Use of P-31 magnetic resonance spectroscopy to detect metabolic abnormalities in muscles of patients with fibromyalgia. Arthritis Rheum. 1998; 41:406-413. Leij-Halfwerk S, Agretesch HJ, Sijens PE, and Dagnelie PC: Adenosine triphosphate infusion increases liver energy status in advanced cancer patients: an in vivo 31P magnetic resonance spectroscopy study. Hepatology 2002; 35:421-424).

2. Administration of ATP in humans was proven to increase deficient organ, blood and skeletal muscle ATP pools (Haskell CM, Wong M, Williams A, Lee LY: Phase I trial of extracellular adenosine 5¢-triphosphate in patients with advanced cancer. Medicinal and Pediatric Oncology 1996; 27:165-173. Agretesch HJ, Dagnelie PC, Rietveld T, van den Berg JWO, Danser AHJ, Wilson JHP: Pharmacokinetics of intravenous ATP in cancer patients. Eur. J. Clin. Pharmacol. 2000; 56:49-55. Leij-Halfwerk S, Agretesch HJ, Sijens PE, Dagnelie PC: Adenosine triphosphate infusion increases liver energy status in advanced cancer patients: an in vivo 31P magnetic resonance spectroscopy study. Hepatology 2002; 35:421-424).


Passwater: In the next interview we will discuss the potential of ATP in benefiting conditions that are directly related to aging. Specifically, peripheral arterial disease (PAD), arthritic diseases, type 2 diabetes and its clinical complications, muscle mass and muscle function, cerebral circulation and mental acuity, skin aging and superfluous fat deposits.WF


© 2006 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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