Document Detail


Interactions of liposome-incorporated amphotericin B with kidney epithelial cell cultures.
MedLine Citation:
PMID:  3419424     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The polyene antibiotic amphotericin B (AmB) is profoundly cytotoxic to both fungal cells and mammalian cells. We have previously shown that the incorporation of AmB into phospholipid vesicles can markedly reduce the toxicity of the drug for mammalian cells (erythrocytes) without changing its antifungal potency [Mol. Pharmacol. 31:1-11 (1987)]. Because the primary site of in vivo toxicity of AmB is the kidney, here we investigate the effects of free AmB and liposomal AmB (L-AmB) on LLCPK1 cells, a porcine kidney cell line with many characteristics typical of proximal tubule cells. Acute exposure (2 hr) to free AmB inhibits protein synthesis and causes cell detachment and protein loss in LLCPK1 cells, with an IC50 of about 30 micrograms/ml. By contrast, certain formulations of L-AmB have little effect on protein synthesis/protein loss at concentrations of up to 2 mg/ml. The action of liposomes in protecting against acute AmB toxicity extends to effects on sugar transport and on cellular morphology in differentiated cultured kidney cells. Thus, the IC50 for inhibition of sodium-stimulated glucose transport by free AmB is 1.5 micrograms/ml whereas concentrations of L-AmB up to 1 mg/ml do not inhibit this process. However, chronic exposure of cells to L-AmB results in profound toxic effects as manifested by changes in cellular transport functions and cell morphology. Our results suggest that extended periods of proximity between cells and liposomes permit the transfer to toxic amounts of AmB. This may be of importance to the therapeutic use of AmB, for which protracted courses of drug administration are common.
Authors:
H J Krause; R L Juliano
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular pharmacology     Volume:  34     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  1988 Sep 
Date Detail:
Created Date:  1988-10-26     Completed Date:  1988-10-26     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  286-97     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, University of Texas Medical School, Houston 77025.
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MeSH Terms
Descriptor/Qualifier:
Amphotericin B / administration & dosage,  toxicity*
Animals
Cells, Cultured
Epithelium / drug effects
Kidney / drug effects*,  metabolism,  ultrastructure
Lipids / analysis
Liposomes / administration & dosage*,  analysis
Methylglucosides / pharmacokinetics
Microscopy, Electron, Scanning
Protein Biosynthesis
Swine
Grant Support
ID/Acronym/Agency:
CA 47044/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Lipids; 0/Liposomes; 0/Methylglucosides; 1397-89-3/Amphotericin B

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