Rácz lehel 1985-ben járt Szentgyörgyi Albertnál, ahol komoly bíztatásokat kapott a mannarax kutatások folytatásához.

Továbbá J. A. McLaughlin Szentgyörgyi Albert legközelebbi munkatársa ajánlotta be a Houstoni National Cancer Center-be és a Bangkoki Ethnopharmacológiai Világkongresszusra.

Metabolism and Cancer

ALBERT SZENT-GYÖRGYI
Laborarory for the National Foundation for Cancer Researrh.
Marine  Biological Laboratory.
Woods Hole, Massachusetts 02543

Abstract

All the energy driving life is genetated in the sun by atomitc reactions. Some of this energy reaches our globe in the forn of a radiation commonly called "sunshine." A small part of this sunshine is captured by the photosynthetic apparatus of plants, which use the energy of the radialion for the splitting of water molecules into H and O. By this reaction the sunshine is traded in for a thermodynamic potential, that of H and 0, and so, henceforth the sole source of the energy of life has to be this thermodynamic potential. To keep life góing the energy of this potential has to be released. This can be done by reversing the reaction which produced the potential, reversing the splitting of water and bringing H and O together to form water agaín, that is, oxidizing the hydrogen.

The big energy gap between H and O can be bridged by performing the oxidation of H piecemeal in reversible steps. This oxidation of the hydrogen is the core of the metabolism.
The metabolism was studied in the potato by means ot the " "guaiak reaction," That is, the blue color developed on the cut surface of the tuber wetted by a solution of guaiac resin.

This study has led to ascorbic acid as a member of the chain of redox pairs connecting H and O.
The study of the metabolism in wheat has led to methoxyhydroquinone and dimethoxybenzoquinone,
which also form redox couples and are part of the cháin of reactions connecting the potential of H and O. This chain consists of  hydro- and benzoquinone, 2,6-dimethoxyhydro- and benzoquinone, ascorbic acid and dehydroascorbic acid, and 'NAD and NAD(P)H.

Neither ascorbic acid nor 2,6-dimethoxybenzoquinone has an inhibitory action on cancer, but together they give a strong inhibition. The difference in midpoint potential between the two is rclatively small, and so the electron tarries long in uncoupled transfer state between the two. From this state the electron can be transferred to outside points,_taking with it part of the  energy of the H-O potential. Evidence wich suggestst that the methoxy group is produced in the adrernal cortex, is increasing.

To create a living system we need three things material to build it front, energy to drive it with, and a pattern for putting these together. The energy is produced in the sun by nuclear reactions and reaches our globe in the form of sunshine. Part of this radia­tion is captured by the photosynthetic apparatus of plants, which use its energy for the decomposition of water molecules into their elements, H and O.' By this reaction the sunshine is traded in for a thermodynamic potential, and so, hencef.orth this potential will have to be the source of biological energy. To be able to drive life this energy has to be taken out of the potential and converted into free energy, which is free to drive life.

lntemational Journal of Quantum Chemistry: Quantum Biology Symposium 12, 257-261 (1985)
R 1986 byJhonWiley & Sons. Inc.

The oxygen split off from water is released into the atmosphere in an inactive "triplet" state, while the H is used for the reduction of CO2. The oxygen of CO2 is reduced to water. The carbon is attached to hydrogen, and the units thus generated are polymerized. One H atom per C gives a stable compound if the ends are joined to a ring in every chain of six C atoms forming a benzene ring. Two H atoms per CO also lead to a stable configuration, forming long chains which later become the backbones of the amino acids and proteins. One H per C leads to aromatic and two H's per C lead to aliphatic chemistry. The rings and rods thus formed carry in them the basic qualities of the protein they form.

The 6 C atoms of the benzene ring have together 24 orbitals. Half of there are used for holding the C atoms together. This leaves 12 orbitals for the 6 H atoms. This means thai every H or its electron has two C orbitals to choose from, and will thus be delocalized, highly mobile; and reactive. The core of the benzene ring will thus have the qualities of a,superconductor. The great subtlety of the reactions of protein has its foundation in the structure of benzene.

The benzene rings are homoiopolar. They can be rendered more electropolar by attaching to them two OH groups in 1,2 or 1,4 position. By detaching the H atoms of Chere OH groups, the OH's are transformed into diketones, which are very strong oxidizing agents. The di-OH and diketone together form a redox couple, which can be reversibly reduced and oxidized and has a well-defined midpoint potential.

I was led into this line of work by my study of the metabolism of potatoes 60 years ago. I was a beginner in biochemistry and was impressed by the splendid blue color developed on the cut surface wetted by a solution of guaiac resin. This resin is oxidized to a beautiful blue substance by strong oxidizing agents and was often used for the demonstration of the action of peroxidase. It was also studied by M. W. Onslow [ 1 ] at the Biochemical Laboratory at Cambridge, England. Onslow was led to the conclusion Ihat the peroxidase system is involved in the metabolism of potatoes. I could convince myself that the color could also be explained without peroxidase simply by the action of an oxidase which oxidized catechol to a diquinone, which is a very strong oxidizing agent. To my grief, my good old professor H. G. Hamburger died at this time, and so I showed my paper to his successor who was an animal psychologist and thought thai biochemistry was a waste of time. He offered for my paper his wastepaper basket. I resigned, my job, published, and was ready to give up science.

To my good luck, Sir Frederick Gowland Hopkins also read my paper. He happened to be Honorary Chairman of the International Physiological Congress at Stockholm, Sweden. In his presidential address he discussed my paper [21 and invited me to Cambridge; reopening for me the closing doors of science.

In those days most biochemical papers dealt with animal material. I found vegetal material more attractive and simply. Moreover, I was convinced there can be no basic difference between the potato and the man who eats it: So I tested many plants with guaiac to see whether they gave a color reaction similar to Ihat in potatoes. Ín this search happened to hit on a small group of plants which gave no color with guaiac because theycontained much of`a reducing agent which bleaches the color. I isolated this agent and found it to be vitamin C,called it "ascorbic acid," and got a Nobel.

Part of the other plants which I tested with the guaiac resin gave a color and part of them did not. The color reactieri given by potatoes was thus widely spread iri naturc~ Many of the plants thus had a metabolism similar to that of potatoes, but there was also, y a widely spread metabolism found in half of the plants which was different, andI wanted to know what the difference was due to. So I had to study one of the plants which gave no color with guaiac. 1 chose grass, which attractcd me for several reasons. One of them was that wheat is but a domesticated grass grown yearly on millions of acres.

The germ of wheat has to control áll the substances impottant for the life of this plant and the wheat germ was subjected in the 1950s to a chemical analysis by the chemist, D. J. Cosgrove [3,4) and his associates, who were interested in the chemistry of baking bread. They were good chemists, and their study led them to the identification of two remarkable substances: methoxyhydroquinone and DMBQ, dimethoxybenzoquinone.

Methoxy is a very remarkable atomic group. It can be derived from OH by replacing the H by CH3. It is strongly negative, like hydrogen. In many ways it behaves like OH, butit never gives a diquinole; which is a danger for the plants, being a strong oxidizing agent used by the plants to kill parasites. The subtle animal tissues may prefer methoxy to hydroxy. The introduction of methoxy groups enlarged the list of substances which could be used to connect O and H by reversible redox couples, which made the backbone of the whole metabolism:' The first object of my work thus became the identification of the redox couples which bridged the energy gap between H and O in the metabolism. I believe that my list is now complete.

The fuel of our metabolism is the H of our food. This H is chemically inactive and becomes activated by being linked to NAD or NADP. From here it is transferred to . dehydroascorbic acid by a sulphur-containing enzyme; which seems to have a coenzyme. From AA it is transferred to 2,6-dimethoxybenzoquinone, and from here H is transferred to monomethoxybenzoquinone. The resulting monomethoxyhydroquinone is then linked to oxygen. On the H end of metabolism, AA and NAD play the leading role, while on the oxygen end the methoxy derivatives have the leading role. These two halves of metabolism have to be in balance because it is this balance which decides the charge of the system.

The O induces a positive (+) and the hydrogen or its electron induces a negative (-) charge. The protein being an anodic colloid, a negative charge will tend to loosen up its structure, decrease molecular interaction, lead to the weakening of contact inhibition, and favor disorder, and thus favor also malignant tránsformation. Contrary to this, the prevailing of oxygen activity will have to sltengthen interaction between protein molecules and favor order and stability.

Out of the series of redox couples connecting the H and O of metabolism, the redox couple of dehydroascorbic acid and DMBQ demands closer consideration. It is here that the oxidation power of O and the reduction power of H meet, tending to neutralize one another.: The object of metabolism is not mutual neutralization of forces, but the production of ,energy and the transfer of the energy of the thermodynamic potential of O and H. The difference of the midpoint potential between dehydroascorbic acid and DMBQ is small (30 mV), and so the electron is transferred between the two, but slowly, and the electron stays in the uncoupled transfer state for a relatively long time. Its lifetime can be measured by the ESR spectroseope, in which the uncoupled electrongives a strong signal with. a very long lifetime. Probably, the specific electronic structure of the two substances also favors the uncoupled state, from which the electron can be transferred to any structure which has a place for it. The Ehrlich ascites cancer cell is such a structure, and if its cell is brought close to the electron in the transfer state, the ESR signal is quenched, indicating the transfer of the electron to the cancer cell. Such cancer celis treated with the AA-DMBQ complex lose their infectivity.Contemporary biochemistry has two major puzzles: oxygen activation and AA. Both have close relations to cancer.The puzzle of oxygen activation is this: the oxygen of our atmosphere is in an inactíve triplet state. To enter into reactions, it has to be activated and brought into the singlet state, which, as shown by A. Kban [5], kifls the ceii. How can a substance be part of metabolism when it kills the cell? This is the puzzle. An important puzzle. Warburg [6] was inclined to see in thefailure of oxygen activation the prime cause of cancer.

Our experiments show that the oxygen is activated by methoxyhydroquinone, which activates the copper, present as an impurity in all biological systems. The activated copper in turn activates oxygen, whích is part of a bigger complex which also contains hydrogen atoms which can be oxidized. So the singlet formed does no damage to its surroundíngs. The products of the reaction do not activate oxygen anymore and so do not produce excess singlets. The activation of oxygen by methoxyhydroquinone can be demonstrated by shaking with air a pl-I 7.4 solutíon of methoxyhydroquinone in the presence of paraphenylenediamine, which becomes oxidized into the purpie oxide by activated oxygen.

The puzzle of AA is in the fact that no seríous tnedícal use has been found yet for AA in spite of its wonderful biological activíty..The simpie solution of the puzzle is in the fact that AA in itself is inactive and needs the presence of DMBQ to develop its activity. In normai tissues there is very little DMBQ.
There is increasing evidence that the activity of methoxy compounds is controlled by the cortical part of the adrenal gland. If there findings arc corroborated and extended, then our list of glands of internal secretion will be completed.

]f cancer is the result of a lack of AA-DMBQ, then it should be favorably influenced by the application of the missing charge transfer complex. The experiments [7} show thai the application of this complex has a very strong retarding effect on ascites cancer in mice. 80% of heavily innoculated animals treated with AA-DMBQ recovered, whíle neither AA nor DMBQ in itself had a favorable action.

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