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

Journal Article · Mon May 01 04:00:00 EDT 2000 · Health Physics

DOI:https://doi.org/10.1097/00004032-200005000-00008· OSTI ID:20075780

Durbin, P W; Kullgren, B; Ebbe, S N; Xu, J; Raymond, K N

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.

• Research Organization: Lawrence Berkeley National Lab., CA (US)
• Sponsoring Organization: US Department of Energy; National Institute of Environmental Health Sciences
• DOE Contract Number: AC03-76SF00098
• OSTI ID: 20075780
• Journal Information: Health Physics, Journal Name: Health Physics Journal Issue: 5 Vol. 78; ISSN HLTPAO; ISSN 0017-9078
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AFFINITY
BIOLOGICAL MODELS
CHELATING AGENTS
EVALUATION
KIDNEYS
LIGANDS
RADIONUCLIDE KINETICS
URANIUM