Cystamine, an organic disulfide (RSSR), is among the best of the known radiation-protective compounds and has been used to protect normal tissues in clinical radiation therapy. Recently, it has also proved to be beneficial in the treatment of disorders of the central nervous system in animal models. However, the underlying mechanism of its action at the chemical level is not yet well understood. The present study aims at using the ferrous sulfate (Fricke) dosimeter to quantitatively evaluate, both experimentally and theoretically, the radioprotective potential of this compound. The well-known radiolysis of the Fricke dosimeter by (60)Co γ rays or fast electrons, based on the oxidation of ferrous ions to ferric ions by the oxidizing species (•)OH, HO(2)(•), and H(2)O(2) produced in the radiolytic decomposition of water, forms the basis for our method. The presence of cystamine in Fricke dosimeter solutions during irradiation prevents the radiolytic oxidation of Fe(2+) and leads to decreased ferric yields (or G values). The observed decrease in G(Fe(3+)) increases upon increasing the concentration of the disulfide compound over the range 0-0.1 M under both aerated and deaerated conditions. To help assess the basic radiation-protective mechanism of this compound, a full Monte Carlo computer code is developed to simulate in complete detail the radiation-induced chemistry of the studied Fricke/cystamine solutions. Benefiting from the fact that cystamine is reasonably well characterized in terms of radiation chemistry, this computer model proposes reaction mechanisms and incorporates specific reactions describing the radiolysis of cystamine in aerated and deaerated Fricke solutions that lead to the observable quantitative chemical yields. Results clearly indicate that the protective effect of cystamine originates from its radical-capturing ability, which allows this compound to act by competing with the ferrous ions for the various free radicals--especially (•)OH radicals and H(•) atoms--formed during irradiation of the surrounding water. Most interestingly, our simulation modeling also shows that the predominant pathway in the oxidation of cystamine by (•)OH radicals involves an electron-transfer mechanism, yielding RSSR(•+) and OH(-). A very good agreement is found between calculated G(Fe(3+)) values and experiment. This study concludes that Monte Carlo simulations represent a very efficient method for understanding indirect radiation damage at the molecular level.
Cystamine, an organic diamino-disulfide, is among the best of the known radiation-protective compounds, although the underlying molecular mechanisms by which it operates remain poorly understood. This study aims to use the aqueous ferrous sulfate (Fricke) dosimeter to evaluate the protective properties of this compound when present during irradiation by fast incident protons in the energy range of 150 keV – 500 MeV, that is, for “linear energy transfer” (LET) values ranging from ∼72.3 to 0.23 keV/μm. The presence of cystamine in irradiated Fricke solutions prevents the oxidation of Fe2+ ions by the oxidizing species produced in the radiolysis of acidic water, resulting in reduced Fe3+ ion yields. A Monte Carlo computer code is used to simulate the radiation-induced chemistry of the studied Fricke–cystamine solutions under aerated conditions while covering a wide range of cystamine concentrations from 5 × 10−7 to 1 mol/L. Results indicate that the protective activity of cystamine is due to its radical-capturing ability, a clear signature of the strong antioxidant profile of this compound. In addition, our simulations show that at low and intermediate concentrations of cystamine, its protective efficiency decreases with increasing LET, which is consistent with previous work. This finding stems from differences in the geometry of the track structures that change from low-LET isolated spherical “spurs” to high-LET dense continuous cylindrical tracks as LET increases. This study concludes that Monte Carlo simulations represent a powerful method for understanding, at the molecular level, indirect radiation damage to complex molecules such as cystamine.
In the spirit of the radiation chemical "spur model", the lifetime of a spur (τ(s)) is an important indicator of overlapping spurs and the establishment of homogeneity in the distribution of reactive species created by the action of low linear energy transfer (LET) radiation (such as fast electrons or γ irradiation). In fact, τ(s) gives the time required for the changeover from nonhomogeneous spur kinetics to homogeneous kinetics in the bulk solution, thus defining the so-called primary (or "escape") radical and molecular yields of radiolysis, which are obviously basic to the quantitative understanding of any irradiated chemical system. In this work, τ(s) and its temperature dependence have been determined for the low-LET radiolysis of deaerated 0.4 M aqueous solutions of H(2)SO(4) and pure liquid water up to 350 °C using a simple model of energy deposition initially in spurs, followed by random diffusion of the species of the spur during track expansion until spur overlap is complete. Unlike our previous τ(s) calculations, based on irradiated Fricke dosimeter simulations, the current model is free from any effects due to the presence of oxygen or the use of scavengers. In acidic solutions, the spur lifetime values thus obtained are in very good agreement with our previous calculations (after making appropriate corrections, however, to account for the possibility of competition between oxygen and Fe(2+) ions for H˙ atoms in the Fricke dosimeter, an effect which was not included in our original simulations). In this way, we confirm the validity of our previous approach. As expected, in the case of pure, oxygen-free water, our calculated times required to reach complete spur overlap are essentially the same (within uncertainty limits) as those found in acidic solutions. This explicitly reflects the fact that the diffusion coefficients for the hydrated electron and the H˙ atom that are involved in the overall calculation of the lifetime of spurs in neutral or acidic media, respectively, are of similar magnitude over the 25-350 °C temperature range studied.
Fast kinetics and time-dependent yields of the hydrated electron (e(-)(aq)) in pure water under conditions of high temperature and pressure up to the supercritical region were investigated by picosecond and nanosecond pulse radiolysis experiments. More significant decays at short times followed by plateau components at longer times were observed with increasing temperature, suggesting faster spur reaction processes. In supercritical water, it was also found that the e(-)(aq) yields strongly depend on the pressure (density). Comparison of these measurements with Monte-Carlo computer simulations allowed us to identify spur reactions of e(-)(aq) that occur predominantly at high temperatures and also to provide new key information on certain spur model parameters. In particular, the experimental time-dependent e(-)(aq) yields were best reproduced if the electron thermalization distance decreases with increasing temperature. This "shrinkage" of spur sizes at high temperatures was attributed to an increase in the scattering cross sections of subexcitation electrons, likely originating from a decrease in the degree of structural order of water molecules as the temperature is increased.
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