Radioprotective Ability Research Articles

Relative radioprotective abilities of 5-hydroxytryptophan and 5-hydroxytryptamine.

Relative radioprotective abilities of 5-hydroxytryptophan and 5-hydroxytryptamine.

Equilibria in thiol–disulphide interchanges. Part V. Reaction of some aminoethanethiols with 4,4′-dithiobis(benzenesulphonic acid)

Thiol–disulphide interchange reactions generally involve two consecutive competitive equilibria. Equations have been developed that relate the composition of the equilibrium mixture to the equilibrium constants, both for simple interchange and for the case in which the thiol formed in the reaction is ionised. Various relationships are made evident. Determination of only one thiol in the equilibrium mixture does not permit calculation of the constants for the two equilibria, but these constants can be obtained from the concentration of a single thiol species in two equilibrium mixtures derived from different initial concentrations. The equations are applied to the determination of approximate equilibrium constants for the interchange of 2-aminoethanethiol, and of eight derivatives, with 4,4′-dithiobis(benzenesulphonate). There appears to be no obvious correlation between these constants and the radioprotective ability of the substances.

Studies on the Molecular Mechanism of the Radioprotective Effect of Serotonin

In recent years serotonin (5-hydroxytryptamine) has aroused considerable interest among radiobiologists because of its effectiveness in radioprotection, an effect discovered concurrently by Gray et al. (1) and Bacq et al. (2) in rats and mice. Subsequent investigations showed that serotonin also protected in other systems (3). Its dose-reduction factor was found to be larger than that of the known SH agents. Several hypotheses have been proposed to explain the radioprotective mechanism of serotonin. Since serotonin demonstrates pronounced pharmacological properties, its radioprotective action in vivo was thought to involve vasoconstriction and, consequently, tissue hypoxia (1, 4-8). Free radical scavenging (9) and interference with biochemical reactions (10, 11) were discussed as other possibilities. All the hypotheses suggested, however, have been questioned, and none seems to give an unambiguous explanation for the effects observed. Recently, Dukor (3) was able to show that serotonin protection cannot be attributed to hypoxia or free radical scavenging. He proposed instead that complex formation between the radiosensitive target and the protector molecule might be responsible for the observed protection. Because of the importance of serotonin in radiobiology, it is obviously of interest to investigate its mode of action, particularly if such studies lead to the discovery of substances having greater radioprotective abilities but with less pharmacodynamic side effects. Since a number of enzymes have metal ions as part of their active site, one useful line of inquiry is the investigation of complex formation between

AN ENZYMATIC EVALUATION OF THIOL RADIOPROTECTORS

A number of thiol and disulfide compounds have been tested for their ability to inhibit the oxidation of α-ketoglutarate by rat-liver homogenates. In general, a correlation exists between the degree of inhibition and the radioprotective ability of the compound. It is possible that a better correlation exists for the corresponding disulfides.The inhibition involves oxidation of the thiol, and the disulfides were found to be more potent inhibitors than the thiols.There is no change in the ATP level of normal tissues after the administration of aminoethylisothiouronium bromide hydrobromide in vivo, and the protective ability of this compound is not considered to be related to any interference with mitochondrial oxidative phosphorylation. Mitochondrial respiration is, however, inhibited. The results support the mixed disulfide protection theory of Eldjarn and Pihl, and provide a physiologically significant test system for this hypothesis.

Antiradiation Compounds VII: Long-Chain Alkyl Derivatives of 2-Mercaptoethylguanidine

Mono-N-alkyl and N,N'-dialkyl derivatives of 2-mercaptoethylguanidine (MEG) have been synthesized as potential radioprotective agents with the assumption that increase in liposolubility of MEG will improve its radioprotective ability. The compounds were obtained by reaction of bromoethylamine with the appropriate alkylated thiourea to give the corresponding aminoethylisothiouronium bromide hydrobromide, which was rearranged to the desired MEG derivative in alkaline solution. The alkyl MEG hydrobromides, unlike MEGBr itself, could be isolated from aqueous solution. Conversion to the trithiocarbonates generally gave products of better crystalline properties. The structure of the trithiocarbonate of MEG was supported by NMR analysis. Mono-N-alkyl and N,N'-dialkyl derivatives of 2-mercaptoethylguanidine (MEG) have been synthesized as potential radioprotective agents with the assumption that increase in liposolubility of MEG will improve its radioprotective ability. The compounds were obtained by reaction of bromoethylamine with the appropriate alkylated thiourea to give the corresponding aminoethylisothiouronium bromide hydrobromide, which was rearranged to the desired MEG derivative in alkaline solution. The alkyl MEG hydrobromides, unlike MEGBr itself, could be isolated from aqueous solution. Conversion to the trithiocarbonates generally gave products of better crystalline properties. The structure of the trithiocarbonate of MEG was supported by NMR analysis.

ANTIRADIATION COMPOUNDS. II. DITHIOCARBAMATES.

Substituted dithiocarbamic acid derivatives, some of which contain metal- chelating functions additional to the dithiocarbamyl group, were synthesized as potential protective agents against ionizing radiation. It appeared that the additional nitrogen-containing chelating function contributed nothing to the radioprotective ability of dithiocarbamates. The derivatives did not approach MEA dithiocarbamic acid in protective ability. However, significant protection (35 to 40% increase in survival over that of the controls) was afforded by a number of the dithiocarbamic acid derivatives when injected 30 min prior to a radiation dose of 575 to 600 r. The phenyl derivative was completely inactive, but the cyclohexyl analog showed significant protection. Both the BETA - diethylaminoethyl and BETA -hydroxyethylaminoethyl derivatives, as well as the piperazine derivatives showed some protection, but the dimethylaminopropyl derivative was without protective ability. Radiation protection of Escherichia coli cells was assayed using the dithiocarbamic acid derivatives, but no protection was observed except with the BETA -hydroxyethylaminoethyl and BETA - aminoethylpiperazine derivatives. Several of the compounds proved to be unexpectedly toxic in mice. No correlation between dosage and protective ability was evident. All of the dithiocarbamates tested were found to chelate both cupric and ferric ions. However, inclusion of additional nitrogen-containing groups, to provide possiblemore » tridentate chelates, did not appear to increase their protective ability.« less