Document Detail


Toxicity mechanisms of amphotericin B and its neutralization by conjugation with arabinogalactan.
MedLine Citation:
PMID:  22908154     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Amphotericin B (AMB) is an effective antifungal agent. However, its therapeutic use is hampered by its toxicity, mainly due to channel formation across kidney cell membranes and the disruption of postendocytic trafficking. We previously described a safe injectable AMB-arabinogalactan (AG) conjugate with neutralized toxicity. Here we studied the mechanism of the toxicity of free AMB and its neutralization by conjugation with AG. AMB treatment of a kidney cell line modulated the trafficking of three receptors (C-X-C chemokine receptor type 4 [CXCR4], M1 receptor, and human transferrin receptor [hTfnR]) due to an increase in endosomal pH. Similar data were also obtained in yeast but with an increase in vacuolar pH and the perturbation of Hxt2-green fluorescent protein (GFP) trafficking. The conjugation of AMB with AG neutralized all elements of the toxic activity of AMB in mammalian but not in fungal cells. Based on these results, we provide an explanation of how the conjugation of AMB with AG neutralizes its toxicity in mammalian cells and add to the knowledge of the mechanism of action of free AMB in both fungal and mammalian cells.
Authors:
Sarah Kagan; Diana Ickowicz; Miriam Shmuel; Yoram Altschuler; Edward Sionov; Miriam Pitusi; Aryeh Weiss; Shimon Farber; Abraham J Domb; Itzhack Polacheck
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Publication Detail:
Type:  Journal Article     Date:  2012-08-20
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  56     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-17     Completed Date:  2013-04-23     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5603-11     Citation Subset:  IM    
Affiliation:
Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
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MeSH Terms
Descriptor/Qualifier:
Amphotericin B / analogs & derivatives*,  chemistry,  pharmacology*
Animals
Antifungal Agents / chemistry,  pharmacology*
Candida albicans / drug effects*,  growth & development,  metabolism
Cell Survival / drug effects
Cercopithecus aethiops
Chemokines, CXC / metabolism
Dogs
Endosomes / drug effects,  metabolism
Galactans / chemistry,  pharmacology*
Humans
Hydrogen-Ion Concentration
Kidney / cytology,  drug effects*,  microbiology
Madin Darby Canine Kidney Cells
Microbial Sensitivity Tests
Protein Transport / drug effects
Receptor, Muscarinic M1 / metabolism
Receptors, CXCR4 / metabolism
Receptors, Transferrin / metabolism
Species Specificity
Transferrin / metabolism
Vero Cells
Chemical
Reg. No./Substance:
0/Antifungal Agents; 0/Chemokines, CXC; 0/Galactans; 0/Receptor, Muscarinic M1; 0/Receptors, CXCR4; 0/Receptors, Transferrin; 0/Transferrin; 0/amphotericin B-arabinogalactan conjugate; 1397-89-3/Amphotericin B
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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