Orally Administered Ethane-1-Hydroxy-1,1-Biphosphonate Reduces the Lethal Effect of Oral Uranium Poisoning

Abstract

Intoxication with uranium compounds is both an occupational risk for the workers engaged in the different processes of the elaboration of nuclear fuel and a risk for the population at large in terms of contaminated water and food. The toxic effects of uranium can be reduced by the administration of a biphosphonate, ethane-1-hydroxy-1,1-biphosphonate (EHBP), subcutaneously or intraperitoneally. The aim of the present work was to examine whether orally administered EHBP reduces the lethal effect of a single orally administered toxic dose of uranyl nitrate. Nine groups of 20 male Balb-c mice were used. Five groups received 350 mg kg(-1) of uranyl nitrate orally administered by gavage, four were co-treated 20 min later with EHBP either by gavage (350, 500, or 700 mg kg(-1)) or by subcutaneous injection (50 mg kg(-1)), and one group was not treated. Four groups of animals received only EHBP in doses and routes the same as those used in the intoxicated animals. Survival was assessed for 14 d. On day 14 the surviving animals of all groups were killed. An additional group of uranium intoxicated animals was killed on day 2 after the start of the experiment. Kidneys were examined histologically. On day 3 all the animals treated with uranyl nitrate alone and 20% of the animals treated with 700 mg kg(-1) of EHBP alone were dead. Survival at day 14 of the groups of mice intoxicated with uranyl nitrate and treated with EHBP (50 mg kg(-1) orally or 50 mg kg(-1) subcutaneously) was 45.0 and 49.6%, respectively. Tubule necrosis lesions were present in kidneys of mice intoxicated with uranyl nitrate, whereas lesions were less severe in mice treated with EHBP. Oral administration of EHBP is effective for reducing the lethal effect of uranium, and it is at least as useful as subcutaneous administration for prompt therapy of oral uranium exposure, achieving a survival rate of almost 50%.

Intracellular Metabolism of Uranium and the Effects of Bisphosphonates on Its Toxicity

“…Bioavailable uranium could link to EHBP in blood conforming chelates that allow uranium to be excreted supressing its effect as a life-threatening compound. Our group has extensive evidence on the preventive effect of EHBP for acute uranium intoxications administered intraperitoneally (Ubios et al, 1994), subcutaneously (Ubios et al, 1998;Martinez et al, 2000) or orally (Martinez et al, 2000). In all cases we demonstrated that EHBP is able to ameliorate the structural and functional damages induced by uranium.…”

“…The longest survival time was observed for suckling animals (Ubios et al, 1994) when compared to adult animals (Martinez et al, 2000). Again, the efficiency of the treatment depended on the time lapse between exposure to the toxicant and the administration of the bisphosphonate proving that efficency is inversely proportional to the time interval (Ubios et al, 1998).…”

“…Several compounds ranging from natural and simple such as sodium citrate, to more sophisticated synthetic chelators agents have been tested in order to treat uranium contamination. To date, several studies have been performed to determine the effectiveness of different chelating agents in preventing the toxic effets of uranium on the body (Domingo et al, 1990;Cabrini et al, 1984;Stradling et al, 1991;Martinez et al, 2000;Bozal et al, 2005). However, not all chelating compound tested showed to be effective to counterbalance the action of uranium.…”

Chelating Agents Used for Plutonium and Uranium Removal in Radiation Emergency Medicine

“…Many chelating agents such as 3,4,3-LIHOPO [19,[34][35][36], Tiron [37,38], ethane-1-hydroxy-1,1-bisphosphonate (EHBP) [39][40][41]46], deferiprone (L1) 1,2-dimethyl-3-hydroxypyrid-4-one [42], DTPA [43], CBMIDA [44] and 1,2-diamino cyclohexyl-tetramethylenetetraphosphonate (CTTP) [45] have been examined for the removal of uranium (Table 4). Although DPTA is often said that it can remove uranium from the body, its effectiveness remains unclear…”

Symmetrical 1,3-dicarbonyl biscatecholamide ligands as sequestering agents for uranyl decorporation

“…Several uranyl ligands had been synthesized based on different complexing functions (containing ethane-1-hydroxy-1,1-bisphosphonate and methylterphthalimide metal binding units). However, their high toxicity or low decorporation efficacy is not suitable for biological decorporation [7][8][9][10][11]. The use of multidentate ligands containing the catecholate functionality as binding units, such as sulfocatechol tiron (4,5-dihydroxy-3,5-benzenedisulfonate), which were of a low to mild toxicity [12][13][14] and can reduce uranium in the body of animals when promptly injected [15][16][17], and the U(VI)-catechol complex (Log K ML = 15.9), which is favorably stable within the physiological pH range [18], might be effective for the in vivo chelation of U(VI).…”