Protective effects of 2-aminoethylthiosulfuric acid and structurally analogous organosulfur compounds against ionizing radiation

Abstract

High efficacy and minimal toxicity radioprotectors are desirable options for the hazards posed by nuclear medical and energy technologies and the dangers presented by nuclear weapons in an unstable global situation. Although cysteamine is an effective radioprotector, it has considerable toxicity. In this study, the protective effects of the less toxic organosulfur compounds 2-aminoethylthiosulfate (AETS), thiotaurine (TTAU), and hypotaurine (HTAU) against X-ray damage in mice were compared with that of cysteamine. Intraperitoneal injection of either AETS or cysteamine (2.2 mmol/kg body weight) 30 min before X-ray irradiation (7.0 Gy) provided 100% survival for 30 days, limited the decrease in erythrocytes and neutrophils over 9 days, and reduced damage to bone marrow and spleen over 9 days. Neither TTAU nor HTAU provided any protection. In mice, 30 min after AETS administration, non-protein thiol content increased in the spleen, indicating cysteamine generation by AETS hydrolysis, the active protective species of AETS. All examined compounds scavenged ^•OH under diffusion control in aqueous solution, which is inconsistent with the difference in the protective effects among the compounds. The results indicate that AETS protects animals from ionizing radiation by several mechanisms, including scavenging ^•OH as cysteamine.

Keywords: radiation protective agent; radical scavenger; reactive oxygen species; sulfuric compound; thiosulfate ester.

Fig. 1.

Chemical structures of organosulfur compounds.

Fig. 2.

Effects of organosulfur compound pre-administration on the survival rate of mice after X-ray irradiation. (A, C) AETS or cysteamine was intraperitoneally administrated 30 min before whole-body X-ray irradiation at 7.0 Gy (Ir) or sham irradiation (Non-ir). (B, D) TTAU, HTAU, and saline was intraperitoneally administrated 30 min before whole-body X-ray irradiation at 7.0 Gy (Ir) or sham irradiation (Non-ir). Data for saline in B are replotted in D. (A, B) Doses were 7.3 mmol/kg body weight (b.w.) for HTAU and 1.1 mmol/kg b.w. for other compounds (low dose experiment). (C, D) Doses were 14.7 mmol/kg b.w. for HTAU and 2.2 mmol/kg b.w. for other compounds (high dose experiment). Survival number of 10 mice per group was counted every day for 30 days.

Fig. 3.

Effects of pre-administration of organosulfur compounds on the number of blood cells of mice after X-ray irradiation. High doses of organosulfur compounds were administered intraperitoneally 30 min before whole-body X-ray irradiation at 7.0 Gy. Blood cells were counted 9 days after the radiation. Open and hatched columns indicate the numbers of cells for sham and X-ray irradiated mice, respectively. The data were expressed as mean ± SD. Significant differences of p<0.05 and p<0.01 obtained using Dunnett’s test are indicated by * and **, respectively.

Fig. 4.

Effects of organosulfur compound pre-administration on the tissue damage in mice after X-ray irradiation. High doses of organosulfur compounds were administered intraperitoneally 30 min before whole-body X-ray irradiation at 7.0 Gy. HE staining of bone marrow (A) and spleen (B) sections were performed 9 days after irradiation. WP and RP indicate white pulp and red pulp, respectively. (C) The spleen was removed 9 days after irradiation and weighed. Significant differences of p<0.01 obtained using Dunnett’s test are indicated by **.

Fig. 5.

Non-protein thiol content in tissues and blood plasma after organosulfur compound administration. High doses of organosulfur compounds were administered to mice intraperitoneally. Non-protein thiol contents in the spleen (A), liver (B), and blood plasma (C) were measured 30 min after administration. Significant differences of p<0.05 and p<0.01 obtained using Dunnett’s test are indicated by * and **, respectively.

Fig. 6.

ESR spectra of the DMPO adducts of oxygen radicals measured in the presence of organosulfur compounds. Hydroxyl radicals were generated by either Fenton reaction (Fenton) or UV-induced photolysis of hydrogen peroxide (UV irradiation), with superoxide anion radical generation by the HX-XOD method (HX/XOD). The organosulfur compound concentration was 3 mmol/L. DMPO concentration for the Fenton reaction was 2.5 mmol/L, and HX/XOD reaction was performed in the presence of 100 μmol/L DTPA. Other conditions are mentioned in Materials and Methods. The signal indicated by h in each spectrum indicates the signal used to obtain the IC₅₀.