title: Efficacy of a novel chelator BPCBG for removing uranium and protecting against uranium-induced renal cell damage in rats and HK-2 cells.
abstract: Chelation therapy is a known effective method to increase the excretion of U(VI) from the body. Until now, no any uranium chelator has been approved for emergency medical use worldwide. The present study aimed to evaluate the efficacy of new ligand BPCBG containing two catechol groups and two aminocarboxylic acid groups in decorporation of U(VI) and protection against acute U(VI) nephrotoxicity in rats, and further explored the detoxification mechanism of BPCBG for U(VI)-induced nephrotoxicity in HK-2 cells with comparison to DTPA-CaNa₃. Chelating agents were administered at various times before or after injections of U(VI) in rats. The U(VI) levels in urine, kidneys and femurs were measured 24 h after U(VI) injections. Histopathological changes in the kidney and serum urea and creatinine and urine protein were examined. After treatment of U(VI)-exposed HK-2 cells with chelating agent, the intracellular U(VI) contents, formation of micronuclei, lactate dehydrogenase (LDH) activity and production of reactive oxygen species (ROS) were assessed. It was found that prompt, advanced or delayed injections of BPCBG effectively increased 24 h-urinary U(VI) excretion and decreased the levels of U(VI) in kidney and bone. Meanwhile, BPCBG injection obviously reduced the severity of the U(VI)-induced histological alterations in the kidney, which was in parallel with the amelioration noted in serum indicators, urea and creatinine, and urine protein of U(VI) nephrotoxicity. In U(VI)-exposed HK-2 cells, immediate and delayed treatment with BPCBG significantly decreased the formation of micronuclei and LDH release by inhibiting the cellular U(VI) intake, promoting the intracellular U(VI) release and inhibiting the production of intracellular ROS. Our data suggest that BPCBG is a novel bi-functional U(VI) decorporation agent with a better efficacy than DTPA-CaNa₃.
authors: Institute of Radiation Medicine, Fudan University, Shanghai 200032, PR China.
authors: Yizhong
authors: Y
authors: Bao
authors: Dan
authors: D
authors: Wang
authors: Zhiming
authors: Z
authors: Li
authors: Yuxing
authors: Y
authors: Hu
authors: Aihong
authors: A
authors: Xu
authors: Quanrui
authors: Q
authors: Wang
authors: Chunlin
authors: C
authors: Shao
authors: Honghong
authors: H
authors: Chen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001822:Body Burden; D002460:Cell Line; D002614:Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015913:Chelation Therapy / Q000379:methods*; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007267:Injections; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced / Q000187:drug effects; D009942:Organometallic Compounds; D004369:Pentetic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014508:Urea / Q000097:blood
chemical_list: D015415:Biomarkers; D002614:Chelating Agents; C581517:N,N'-1,2-ethanediylbis(N-((2,3 -dihydroxyphenyl)methyl))glycine; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C005460:uranyl acetate; D004369:Pentetic Acid; D014508:Urea; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D005998:Glycine