Butler and liberation of inorganic phosphate; 5 occurs normally as a consequence of 4 Scholes and WeisSj ; Butler and Conway, All these chemical effects are primarily radical reactions and can be produced by — OH radicals formed in other ways. The reactions of — H are not so well defined, except in so Fig. The liberation of inorganic phosphate varies with the square of the dose, as is to be expected since iwo phosphate ester bonds have to be broken in order to liberate PO 4 Butler and Conway, It is not easy to demonstrate directly the breakage of the nucleotide chains. The effect of single breakage is to liberate a terminal phosphate group, but it can be shown that after irradiation free phosphate is more quK'kly liberated on acid hydrolysis Butler and Simson, ; set also Fig.
Butler up in the fact that heat denaturation occurs more easily after irradiation Fig. Pain on materials irradiated by Prof. It is clear that this is a fair! Butler know what the function of this part of the nucleoprotein system is.
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The influence of this protein -on radiation effects is not easily assessed. It might be expected a prioii that histone would have a protective effect on DNA by mopping up radicals, which would be prevented from reaching the DNA. No accurate experiments on this have been made as it is difficult to be sure that DNA has been recovered quantita- tively from the nucleoprotein, and slow degradative changes occur m the nucleoprotein on standing. It may be useful to estimate the degree of damage in the chromosome particle by different processes.
In the hydrated state m the presence of water it may be expected that this -will be increased by several times at least, i.
Isotopes in Biochemistry
This means that a considerable amount of damage can be done to a DNA particle without affecting a specific gene carried by it. There are, of course, great uncertainties in many of the quantities entering into this calculation. AMtso ni. However, it is obvious tlint reaction with DNA and RNA will not only interfeie with their ability to reproduce themselves but also with their metabolic functions.
ENpenments fay G. Hunter and A. R Crathom. We tried to repeat that, but we were not able to detect any difference in the isolated DNA Wliat happens, of course, is that the ladiation kills the cells and you may get DNA which has been metabolically damaged by enzymes from dj ing cells Forssberg. In vita ii radiation sometimes causes a marked degradation. In another experiment the effect of radiation on a dilute solution of an artificial nucleoprotcin obtained by mixing calf thv mus DN.
After exposure to 1 , r the fall in viscosity was very much greater in the former case, tliat is, when the nucleoprotcin was irradiated. Dr Hoi! In the curve sliomi in Fig. Now if AET is added Fig. With r lower curve more AET is needed for maximal protection Much more complete protection is observed with lower doses of radiation. Fisher, unpublished.
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There is, honever, a viscosity change which AET mil not protect against. Lajtha mentioned the effect of the irradiation of the spleen. Is this effeet not due to an interference Avith the formation of a humoral substance and is the much greater effcctiA'cncss of the v hole- body radiation not partly due to the supression of the formation of tins substance in the aaIioIc organism? A to radiation, Aihich has been stressed by Butler, is more apparent than real.
Stacey Jtadiohwl , Chimbridgc, , B E. From a series of measurements we find that for every electron volts deposited in the nucleic acid or a G value of more than 5 one break occurs in the mam chain if the DNA is irradiated in the solid state. In other words, direct action is about 50 times more effective than indirect action for depolymerizmg DNA. In the cell where the DNA is present at relatively high local concentration, direct action will be much more important than indirect action as far as depolymerization is concerned.
This is relevant to the point made by Prof. Mitchell see p. Experiments which were carried out on a transforming agent of Pneumococcus by Dr.
Ephrussi-Taylor and myself are not in agreement with what Dr. Alexander has just said. The purified transforming agent, which IS DNA, is tested not by physicochemical properties but by its biological specific activity, and its sensitivity to radiation remains the same whether it has been treated with 5 m urea or not.
Since synthetic processes in the nucleus are generally considered to be dependent on energy- generating reactions which occur m the cytoplasm, it was thought possible that the disturbance of nuclear functions which occurs after irradiation might be the result of damage to biochemical reaction systems outside the nucleus. The cytoplasmic reaction chains by which energy is produced in a transportable form, e. In terms of the production of high energy phosphatn-honds, the latter are by far the most important.
The older literature con- tains some reports on morphological changes in mitoehondria which w'ere obseived shortly after irradiation of plant and animal cells Nadson and Rochlin, ! The changes described are presumably non- specific but this applies to most of the radiation-induced nuclear changes as well. Several of the authors claim that the mitochondrial effects precede the morphological changes which occur in the nuclei.
On the other hand, Troivell in a recent investigation of the effect of radiation on lympho- cytes has reported only minor changes of the mitochondria. In studies were initiated in this laboratory with the object of collecting information on the effects of ionizing radiation on the oxidative phosphorylations. In preliminary experiments vith mitochondria from various tissues, a decreased phosphorylation was observed in rat spleen mito- chondria aftcT total body irradiation van Bekkum et ah, Most of our subsequent ivork has been carried out vith rat spleen mitochondria but this effect has also been demon- strated in mitochondria from mouse spleen and rat thymus.
In recent experiments the gas phase was air, which did not make any difference. For a detailed description of these methods reference is made to previous papers van Bekkum et ah, ; van Bekkum and Vos, It should be pointed out that the properties of spleen and thymus mitoehondria are not identieal with those of hver mitochondria. IWorphological differences have been observed : spleen mitoehondria are smaller and of less uniform size. The number of mitochondria per cell is distinetly smaller in spleen and thymus than in liver, and accordingly the yield of mitochondria from the former tissues is much smaller.
Finally the phosphorylating activity of spleen mitochondria may vary considerably between individual rats. This is probably partly due to the marked variation of the cellular composition of the spleen in rats. In order to minimize the effect of these variations, the mitochondria were prepared from the pooled spleens or thymus glands of rats. Furthermore, in every experiment, control and irradiated tissues were handled simultaneously. Results In our earlier experiments the relatively large dose of r of total body irradiation was administered; 4 hours thereafter tlie rats were killed and the isolation of the spleen mitochon- dria vas started.
A significant depression of the phosphate uptake v. VAN Bekkum These eonsisted of pyknosis, fragmentation and vacuolization of the nuclei of a small number of thymocytes.
The number of mitotic figures was decreased by about 50 per cent m the irradiated group. This amount of nuclear degenera- tion seems rather small to explain the observed changes of the mitochondrial functions. It was concluded that the oxidative phosphorylation in these tissues represents a c rtopIasmic function the radiosensitivity of which is comparable to that of the nuclei. The interval between irradiation and the appearance of the effect Because of the possible relation between nuclear metabolism and oxidative phosphorylation it seemed of interest to investi- gate whether the disturbance of the latter becomes discern- ible prior to or after the beginning of nuclear degeneration.
This was studied on spleen tissue after a total body dose of r van Bekkum and Vos, Measurements were made at 15 minutes, 30 minutes, 1, 2 and 4 hours after irradiation. The earliest significant depression of phosphate uptake was found at 2 hours Fig. The histological findings may be summarized as folloivs: from 15 minutes up to 2 hours after irradiation the niitotic frequency was greatly diminished, at 4 hours some reappearance of mitotic figures was noted. Signs of nuclear degeneration Avere absent or dubious at la and 30 minutes after irradiation.
After 1 hour early stages of nuclear degeneration became clearly discernible in a fev cells.
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Nucleai damage could thus clearly be observed before a significant dccrea-se of phosphor 5 dation Avas demonstrable. Tins, hoAvcA'cr, cannot be taken as proof that nuclear degen oration precedes the mitochondrial lesion. Because indiAudua 81 D. The postirradiation interval was 4 hours in all eases because after longer periods secondary clTccts may be expected. So far, the disturbance has only been found in spleen and thymus mitochondria. Results with liver, regenerating liver and a number of transplantable mouse tumours were negative even after doses of several thousands of r.
Intestinal mucosa and bone marrow did not yield satisfactory mitochondrial preparations so that these tissues could not be studied. A depression of oxidative phosphorylation was found, which was comparable to that observed after total body irradiation, and therefore the elTcct is at least chiefly due to the action of X-rays on the spleen cells directly.
Isotopes in Biochemistry
As to the nature of the cells containing these sensitive mitochondria, evidence has been presented that the mitochondria from both lymphoid and erythropoietic cells are susceptible to irradia- tion van Bekkum, a. It has not been possible to reproduce the clTcct of radia- tion on the mitochondria in vitro, even with doses as large as 20, r. Similar negative findings have been reported by Potter and Bethel and by Ord and Stocken On the nature of the mitochondrial defect The possibility has been considered that decreased phos- phorylation after irradiation might be artificially induced during the isolation process, as a result of some unknown and completely unrelated change of the irradiated tissues, c.
Therefore an attempt was made to measure the rate of phosphorylation in vivo by the use of radioactive phosphate.
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VAN Bekkuji between the eonliol and the irradiated groups. Similar lesults have been obtained with this technique in thymus glands. An increase of ATPase activity in spleen homogenates after total body irradiation has been reported by several authors Ashwell and Hickman, ; Dubois and Petersen, and the question arose whether the depression of oxida- tive phosphorylation might be related or even secondary to this phenomenon. A more detailed investigation showed that.. Finally Petersen, Fish and Dubois reported that the ATPase effect is absent after iriadiation of the exteiiorized spleen exclusively and it should therefore be classified among the secondary radiation effects.
It vas concluded that different mechanisms arc probably involved in the development of these biochemical changes. So far.
When cytocliromc c is omitted from the s'ueeinate reaction system both phosphate uptake and oxygen consurnjition drop about 50 per cent in the control prepara- tions. In other nords the addition of cytochrome c causes an apfireciable stimulation cytocliromc c effect. VAN Bekkum of cytoclirome c being aggravated as a result of irradiation, the cytoehrome c effect was estimated at 2 hours after irradiation in unwashed mitochondria.
Therefore this simple explanation cannot be applied. It is also to be noted that irradiation docs not result in an increased leakage of DPN. Conclusions At present we arc still far from a complete understanding of the biochemical changes that take place in spleen mito- chondria after irradiation.