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Title: Chelating agents for uranium(IV): 2. Efficacy and toxicity of tetradentate catecholate and hydroxypyridinonate ligands in mice

Abstract

Uranium(VI) (UO{sub 2}{sup 2+}, uranyl) is nephrotoxic. Depending on isotopic composition and dosage, U(VI) is also chemically toxic and carcinogenic in bone. Several ligands containing two, three, or four bidentate catecholate or hydroxypyridinonate metal binding groups, developed for in vivo chelation of other actinides, were found, on evaluation in mice, to be effective for in vivo chelation of U(VI). The most promising ligands contained two bidentate groups per chelator molecule (tetradentate) attached to linear 4- or 5-carbon backbones (4-LI, butylene; 5-LI, pentylene; 5-LIO, diethyl ether). New ligands were then prepared to optimize ligand affinity for U(VI) in vivo and low acute toxicity. Five bidentate binding groups--sulfocatechol [CAM(S)], carboxycatechol [CAM(C)], methylterephthalamide (MeTAM), 1,2-hydroxypyridinone (1,2-HOPO), or 3,2-hydroxypyridinone (Me-3,2-HOPO)--were each attached to two linear backbones (4-LI and 5-LI or 5-LIO). Those ten tetradentate ligands and octadentate 3,4,3-LI(1,2-HOPO), an effective actinide chelator, were evaluated in mice for in vivo chelation of {sup 233}U(VI) (injection at 3 min, 1 h, or 24 h or oral administration at 3 min after intravenous injection of {sup 233}UO{sub 2}Cl{sub 2}) and for acute toxicity (100 {micro}mol kg{sup {minus}1} injected daily for 10 d). The combined efficacy and toxicity screening identified 5-LIO(Me-3,2-HOPO) and 5-LICAM(S) as the most effective low-toxicitymore » agents. They chelate circulating U(VI) efficiently at ligand:uranium molar ratios {ge} 20, remove useful amounts of newly deposited U(VI) from kidney and bone at molar ratios {ge} 100, and reduce kidney U(VI) levels significantly when given orally at molar ratios {ge} 100. 5-LIO(Me-3,2-HOPO) has greater affinity for kidney U(VI) while 5-LICAM(S) has greater affinity for bone U(VI), and a 1:1 mixture (total molar ratio = 91) reduced kidney and bone U(VI) to 15 and 58% of control, respectively--more than an equimolar amount of either ligand alone.« less

Authors:
; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab., CA (US)
Sponsoring Org.:
USDOE; National Institute of Environmental Health Sciences
OSTI Identifier:
20075780
DOE Contract Number:  
AC03-76SF00098
Resource Type:
Journal Article
Journal Name:
Health Physics
Additional Journal Information:
Journal Volume: 78; Journal Issue: 5; Other Information: PBD: May 2000; Journal ID: ISSN 0017-9078
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; URANIUM; CHELATING AGENTS; KIDNEYS; RADIONUCLIDE KINETICS; BIOLOGICAL MODELS; LIGANDS; AFFINITY; EVALUATION

Citation Formats

Durbin, P.W., Kullgren, B., Ebbe, S.N., Xu, J., and Raymond, K.N. Chelating agents for uranium(IV): 2. Efficacy and toxicity of tetradentate catecholate and hydroxypyridinonate ligands in mice. United States: N. p., 2000. Web. doi:10.1097/00004032-200005000-00008.
Durbin, P.W., Kullgren, B., Ebbe, S.N., Xu, J., & Raymond, K.N. Chelating agents for uranium(IV): 2. Efficacy and toxicity of tetradentate catecholate and hydroxypyridinonate ligands in mice. United States. doi:10.1097/00004032-200005000-00008.
Durbin, P.W., Kullgren, B., Ebbe, S.N., Xu, J., and Raymond, K.N. Mon . "Chelating agents for uranium(IV): 2. Efficacy and toxicity of tetradentate catecholate and hydroxypyridinonate ligands in mice". United States. doi:10.1097/00004032-200005000-00008.
@article{osti_20075780,
title = {Chelating agents for uranium(IV): 2. Efficacy and toxicity of tetradentate catecholate and hydroxypyridinonate ligands in mice},
author = {Durbin, P.W. and Kullgren, B. and Ebbe, S.N. and Xu, J. and Raymond, K.N.},
abstractNote = {Uranium(VI) (UO{sub 2}{sup 2+}, uranyl) is nephrotoxic. Depending on isotopic composition and dosage, U(VI) is also chemically toxic and carcinogenic in bone. Several ligands containing two, three, or four bidentate catecholate or hydroxypyridinonate metal binding groups, developed for in vivo chelation of other actinides, were found, on evaluation in mice, to be effective for in vivo chelation of U(VI). The most promising ligands contained two bidentate groups per chelator molecule (tetradentate) attached to linear 4- or 5-carbon backbones (4-LI, butylene; 5-LI, pentylene; 5-LIO, diethyl ether). New ligands were then prepared to optimize ligand affinity for U(VI) in vivo and low acute toxicity. Five bidentate binding groups--sulfocatechol [CAM(S)], carboxycatechol [CAM(C)], methylterephthalamide (MeTAM), 1,2-hydroxypyridinone (1,2-HOPO), or 3,2-hydroxypyridinone (Me-3,2-HOPO)--were each attached to two linear backbones (4-LI and 5-LI or 5-LIO). Those ten tetradentate ligands and octadentate 3,4,3-LI(1,2-HOPO), an effective actinide chelator, were evaluated in mice for in vivo chelation of {sup 233}U(VI) (injection at 3 min, 1 h, or 24 h or oral administration at 3 min after intravenous injection of {sup 233}UO{sub 2}Cl{sub 2}) and for acute toxicity (100 {micro}mol kg{sup {minus}1} injected daily for 10 d). The combined efficacy and toxicity screening identified 5-LIO(Me-3,2-HOPO) and 5-LICAM(S) as the most effective low-toxicity agents. They chelate circulating U(VI) efficiently at ligand:uranium molar ratios {ge} 20, remove useful amounts of newly deposited U(VI) from kidney and bone at molar ratios {ge} 100, and reduce kidney U(VI) levels significantly when given orally at molar ratios {ge} 100. 5-LIO(Me-3,2-HOPO) has greater affinity for kidney U(VI) while 5-LICAM(S) has greater affinity for bone U(VI), and a 1:1 mixture (total molar ratio = 91) reduced kidney and bone U(VI) to 15 and 58% of control, respectively--more than an equimolar amount of either ligand alone.},
doi = {10.1097/00004032-200005000-00008},
journal = {Health Physics},
issn = {0017-9078},
number = 5,
volume = 78,
place = {United States},
year = {2000},
month = {5}
}