CHEMICAL & ENGINEERING
NEWS VOLUME 39, NUMBER 14
The Chemical World This Week
APRIL 3, 1961
New Theory Explains Radiation Damage Chelation of copper in vital enzymes may protect against radiation; chelates show promise elsewhere in medicine 139TH
ACS
NATIONAL
MEETING
Medicinal Chemistry
Cu(l) Chelation A new theory of how radiation damages living cells provides clues to how to design protective chemicals. Key to the theory is the copper present in strategic copper enzymes, especially cytochrome oxidase, an enzyme found in cell mitochondria, which provides energy for cell metabolism by reacting with molecular oxygen to form water. Organic peroxides formed by ionizing radiation, Dr. Jack Schubert of Argonne National Laboratory postulates, oxidize the cuprous ion in the enzyme to cupric ion. In the oxidized state, the enzyme can't interact with oxygen so cell metabolism is impaired. Dr. Schubert's theory also states that protection can be attained by two other mechanisms: depletion of oxygen in the tissues and direct destruction of organic peroxides. Both mechanisms involve diminution of the concentration of radiation-produced organic peroxides. Some chemicals act through a combination of these mechanisms, says Dr. Schubert. Stabilization of cuprous copper and direct peroxide destruction can protect against all types of ionizing radiation—x-rays, neutrons, and gamma rays —even when given after exposure, Dr. Schubert says. Oxygen depletion cannot protect against neutrons or after exposure to radiation. The new theory offers a unified mechanism to explain the effects of radiation on cell components. It ties together experimental findings of other observers to an "unprecedented de-
Oxygen Depletion or Peroxide Scavenging
Degree of Protection
Concentration of Drug Theory predicts that drug's concentration will affect the degree of protection it offers against killing doses of radiation. Drugs that chelate or complex cuprous ion, or destroy organic peroxides directly, should protect against x-rays, gamma rays, and neutrons, while those that act by oxygen depletion should protect against x-rays and gamma radiation
gree," Dr. Schubert told the Symposium on Chelating Agents in Medicine. Some chemicals form stable yet dissociable chelates with cuprous ion. The chelated copper is thus protected from the oxidizing action of organic peroxides produced by radiation. It should be possible now, Dr. Schubert says, to protect against radiation by designing chemicals which can stabilize copper in the cuprous state. Conversely, chemicals which can stabilize cupric copper give increased sensitivity to radiation. Medical uses of chelating agents fall into four general categories. They
can be used to tie up essential metals normally in the body. Used this way, a selective chelating agent can kill parasites, such as fungi and bacteria, by depriving them of vital metals. Chelating agents can also be used to make trace metals available to the body. This way, they can poison a parasite or alleviate a deficiency such as occurs in iron deficiency anemia. Properly designed chelating agents can be used to redistribute vital heavy metals already in the body. This is thought to happen when chelating chemicals are used to treat Wilson's disease. Or chelating agents can be used to APRIL
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Basis of Radiation Protection Scheme Is . . . ENZYME-CUPROUS COPPER + RADIATION
0fga
"' C - * ENZYME-CUPRIC COPPER peroxides
To Protect: Complex Cuprous Copper with . . •
To Sensitize: Complex Cupric Copper with . . .
chemicals forming a dissociable chelate ring in which copper is attached to sulfur and nitrogen or sulfur and sulfur as i n . . . mercaptoamines dithiols or as a complex with cyanide and nitriles or...
Reduce oxygen in tissue, as with . . . sodium hydrosulfite adrenaline serotonin or...
chemicals forming a dissociable chelate ring in which copper is attached to nitrogen and oxygen or nitrogen and nitrogen as in . . . a-alkylalanines or...
Capable of forming undissociable complexes with copper, as with . . . penicillamine cyanide
Scavenge peroxides, as with derivatives of tertiary amines
remove an undesirable metal from the body. This approach is used to treat lead, mercury, and arsenic poisoning. Efforts to hasten excretion of radioelements with chelating chemicals have been fairly successful with triand tetravalent elements, such as thorium, plutonium, and the rare earths, but unsatisfactory with strontium. Protection. Many dissimilar chemicals offer some degree of protection against radiation. Examples include some mercaptoamines, dithiols, dithiocarbamates, and cyanide. Conversely, some dissimilar chemicals—a-alanines, penicillamine, and nitric oxide, for example—increase sensitivity. Some research indicates that radiation does cause organic peroxides to form in the cell. And Dr. Schubert's studies indicate that these organic peroxides oxidize the cuprous ion of cytochrome oxidase irreversibly to the cupric state. This prevents the reaction with oxygen that releases vital energy to the cell. In the past, tests have indicated that high dosages of radiation had no effect on cytochrome oxidase. Dr. Schubert points out, however, that the process of mashing up the test material for analysis releases agents which reduce 26
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oxidized copper, thus reactivating the enzyme. Addition of EDTA to the test material to stabilize the copper before mashing, he says, shows that as little as a few thousand roentgens of radiation inhibits the enzyme. Chemicals which can prevent oxidation of copper should help protect against radiation, Dr. Schubert says. This means that a systematic search for better protective agents should now be possible. One promising approach is to design chelating chemicals which can reach the cell's mitochondria to tie up the cuprous ion in a stable, yet dissociable, complex. Generally, chelating chemicals that form a ring in which copper is attached to sulfur and nitrogen or to two sulfur atoms tend strongly to react with cuprous copper. Chemicals that form a ring with the copper attached to nitrogen and oxygen or to two nitrogens tend to tie up cupric copper. Seeming contradictions to the theory can be explained by the law of mass action or by physiological considerations, Dr. Schubert says. Penicillamine, for example, which has the proper sulfur and nitrogen configuration, would be expected to tie up cu-
prous copper. Yet, it is a sensitizing chemical. The reason is that penicillamine isn't destroyed by the body, so relatively high concentrations of it reach the copper and form nondissociable complexes. Thus, the coppercontaining enzyme is prevented from functioning normally. Cysteine, very similar to penicillamine in structure, is much more readily destroyed by the body, so lower concentrations of it reach the copper. Thus, chelates with cysteine have a chance to dissociate, and cysteine protects against radiation. Salicylic acid, adrenaline, and histamine favor cupric copper, yet they provide protection. Dr. Schubert says they act to reduce oxygen in sensitive tissue, thus reduce the formation of organic peroxides which oxidize enzymatic cuprous copper and damage critical molecules such as nucleic acids. Major Diseases. Chelating agents may one day play a big part in treating major diseases. Investigators point to much circumstantial evidence that metals play a role in cancer. Some metals are known carcinogens. Many of the metabolic products of cancer-causing materials can chelate. Many chemicals now used or being investigated as anticancer agents are
good chelating agents. Metals are intimately tied to several enzyme systems which are vital to cell growth and which could be involved in cancer. Cancer cells, generally, are more responsive to radiation than similar normal cells. Cancer cells are generally lower than normal in cytochrome oxidase, Dr. Schubert says. So far as utilization of energy by the cell is concerned, he adds, less cytochrome oxidase means less protective cuprous copper and, therefore, greater sensitivity to radiation. So to improve cancer therapy, Dr. Schubert suggests selective removal of copper from the cancer cell with a chelating agent. This would make the cell more sensitive to radiation; or if enough copper were selectively removed, the cell would die from lack of the vital metal. Factor in Aging. Aging is accompanied by the accumulation of metals in various organs. It's not beyond reason, some experts believe, that such accumulations alter enzyme reactions, eventually resulting in chronic diseases associated with aging, such as arthritis and hypertension. Dr. Schubert theorizes that available cuprous ion is reduced with age due to irreversible oxidation by natural organic peroxides. Properly designed chelating agents may help fight the diseases of age by reactivating the oxidized copper or by lowering the amount of organic peroxides formed in the body. While chelating agents look intriguing as highly specific, pharmacologically active materials, things aren't usually that simple, cautions Dr. Harold F. Hardman of Marquette University medical school. Dr. Hardman points to theophylline and caffeine, structurally related drugs capable of stimulating the heart. While theophylline is capable of chelating, caffeine isn't. Yet both are equally effective stimulants under experimental lab conditions, he says. Dr. Hardman concludes that theophylline's action isn't based on chelation. Further, Dr. Hardman says, stability constants of potent chelating agents such as EDTA with metals aren't significantly higher than those of natural amino acids in the body with metals. So such chelating agents face a tough job competing with the body for metals, he notes. He also points out that EDTA doesn't readily penetrate mammalian cell walls, while the body's chelating chemicals are already inside the cell. This further complicates the job of unnatural chelating agents.
Council Approves New Meeting Plan Two experimental approaches will be tried; action tabled on Principles of Professional Conduct Last week in St. Louis, the Council of the American Chemical Society approved two experimental changes in the organization and scope of its national meetings: • Limit some meetings to formal presentation of selected papers and hold round-table discussions of the others. • Hold a third national meeting during 1963 and 1964. These experimental changes were recommended to the Council by Dr. W. O. Milligan, chairman of the ad hoc Joint Board-Council Committee on Plans for Future National Meetings, set up nearly two years ago to study the meeting problems caused by the Society's increasing size (C&EN, Oct. 31,1960, page 74). In the first type of meeting experiment, some papers will be scheduled for formal presentation. Others will not be presented formally, but divisions will be provided suitable conference rooms where authors of these papers and those desiring to do so can hold round-table discussions. The usual abstracts of these discussion papers will be printed as at present, and the papers will be listed on the program as discussion papers. Each division will be responsible for deciding which category each paper falls in and for all other rules governing its program. Plans for meetings through 1965 now shape up like this: No changes for the Chicago meeting this fall, the Washington, D.C., meeting in the spring of 1962, the Los Angeles meeting in the spring of 1963, and the New York meeting in the fall of 1963. The Atlantic City meetings in the fall of 1962 and the fall of 1965 and the Chicago meeting in the fall of 1964 will have limited formal presentations with round-table discussions. In addition, the Detroit meeting in the spring of 1965 will be changed from an extended meeting to a one-week meeting, and it, too, will have limited formal presentations and round-table discussions. The spring 1964 meeting in Philadelphia will be rescheduled to one week. A third national meeting will be
held on an experimental basis in both January 1963 and January 1964. Dr. Milligan proposes such cities as Kansas City, Cincinnati, Milwaukee, and Denver as possibilities. None of these sites has been selected as yet, however. Dr. Milligan says these changes will allow each division to hold from two to six meetings with other divisions during 1963 and 1964. Some divisions now hold separate meetings every year or every other year, and other divisions will be encouraged to do the same to serve more geographical areas and to present additional forums for authors. Dr. Milligan also stressed in his recommendations that regional meetings will approach national meetings in stature as they get larger and present programs that are more diversified. Regional meetings will serve as additional outlets for presenting original scientific contributions. Principles Tabled. Under preparation for some two years, the Principles of Professional Conduct were presented to the Council for adoption. Dr. Frederick C. Nachod, chairman of the Council Committee on Professional Relations and Status, which prepared the document, said the committee sees the principles as: • A guide of conduct for practicing chemists and chemical engineers. • A public relations measure to identify chemists' professionally. • An aid to students and those entering the profession to know what is expected of them in nontechnical areas. • A guide for employers of ACS members. In the Council discussion that followed, some councilors agreed, others did not. Those opposed generally took the position that ethics cannot be legislated but only encouraged and that the principles might do more harm than good if the public began wondering why chemists and chemical engineers had to subscribe to a formal document stating what these opponents feel are rather elementary ethics. A motion to table carried, and the matter is now back in the PR&S Committee for further study. APRIL
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Dr. Olaf A. Hougen of the University of Wisconsin, winner of the ACS Award in Industrial and Engineering Chemistry, discusses solid catalysts in his award address
Award Winners Had a Busy Week in St. Louis
Garvan Medal was presented to Dr. Sarah Ratner (right), Public Health Research Institute, by Dr. Essie White Cohn of the University of Denver for Dr. Ratner's work on enzymes and intermediary metabolism
Fisher Award winner Dr. Herbert A. Laitinen, University of Illinois, gave award address at a session of the Division of Analytical Chemistry 28
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Research on coenzyme Q won the Eli Lilly and Co. Award in Biological Chemistry for Dr. Frederick L. Crane (right) of Purdue University. Lilly's Dr. Mack H. McCormick presented the award to Dr. Crane
Dr. Eugene E. van Tamelen (right), University of Wisconsin, gets ACS Award in Pure Chemistry from M. A. Schneller, representing Alpha Chi Sigma
The Priestley Medal, the highest award of the ACS, is proudly displayed by Mrs. Louis P. Hammett, while Dr. Hammett of Columbia University, who won the medal for his "distinguished services to chemistry," looks on APRIL
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Honors; Television Shows; Muted Fireworks in
Dr. David Dietz(left), science editor of Scripps-Howard newspapers, is interviewed on space exploration by Steve Rowan of radio station KMOX. Dr. Dietz later received the James T. Grady Medal
After being named an honorary member of Phi Lambda Upsilon, Dr. Paul D. Bartlett of Harvard University talks to the group's luncheon meeting
Cameras of KMOX-TV train on Dr. Douglas J. Hennessy of Fordham University (left) during interview on his analyses of meteorites
Aiso talking for TV is ACS Executive Secretary Alden H. Emery (right), shown with KMOX-TV's Max Roby
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New routes to boron monoxide and diboron tetrachloride could ease research in diboron chemistry
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lron-55 x-ray absorption determines one highatomic-number element in low-atomic-number matrix
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Column methods of fractionating linear polymers yield molecular weight distribution routinely
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Aliphatic acids with omega-halogen made by ferrous sulfate reduction of hydroperoxides
SEE THESE PAGES FOR A QUICK RUNDOWN ON CHEMICAL NEWS FROM ST. LOUIS
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Council Meeting
ACS members line the balcony of Sheraton-Jefferson Hotel's Gold Room to watch Council meeting in progression the floor below
. . as motions draw comment from the floor
L J. WOOD...meetings help young chemists
F. K. KLEPETAR...in favor of this document
J. M. CHURCH...ready to vote on the motion
A. C. COPE...the President offers a few words
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New route to condensed hydrocarbons supports concept of role of spatial arrangement in reactions
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Synthetic nose is goal of research program based on contact-potential olfactometry instead of biochemical methods
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Less costly zirconium could result from process that yields lowhafnium zirconium tetrachloride
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Aromatic peroxy acids made in high yield from parent acid and hydrogen peroxide in methanesulfonic acid
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Process for making nylon 7 of high molecular weight starts with epsiloncaprolactone
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New types of fungicides are heterocyclic compounds that have two adjacent sulfurs in a five-membered ring APRIL
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