Document Detail

Multiple mechanisms for doxorubicin cytotoxicity on glomerular epithelial cells 'in vitro'.
MedLine Citation:
PMID:  1332879     Owner:  NLM     Status:  MEDLINE    
This study was planned to define the metabolic pathways for free radical production by isolated glomeruli and glomerular epithelial cells in vitro after exposure to cytotoxic doses of doxorubicin. A net increment in glomerular superoxide anion (O2.) synthesis was observed at doxorubicin doses between 10 and 30 micrograms/ml, a drug level which also induced a parallel increment in uric acid synthesis. Since the synthesis of O2. with production of uric acid implies an activity of xanthine oxidase, a few experiments were performed with glomeruli which had been deprived of xanthine oxidase activity. In this case doxorubicin-inducible O2. and uric acid synthesis by glomeruli was practically nil. A similar stimulatory effect of O2. synthesis was induced by doxorubicin on glomerular epithelial cells and also in this case O2. synthesis was suppressed by pre-treating cells with deoxyconformicin, a selective inhibitor of adenosine deaminase. Finally, equimolar amounts of the drug were equally cytotoxic even when kept constantly outside the cell by a stable linkage with an agarose macroporous bed. In summary, these data demonstrate that O2. is generated by isolated glomeruli and glomerular epithelial cells 'in vitro' when exposed to cytotoxic amounts of doxorubicin and that purine degradation to uric acid furnish the metabolic pathways for glomerular O2. generation. However, doxorubicin is comparably cytotoxic on glomerular epithelial cells from outside cells thus suggesting that also a membrane perturbation may activate the series of events leading to cell injury.
G M Ghiggeri; R Bertelli; F Ginevri; R Oleggini; P Altieri; A Trivelli; R Gusmano
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of pharmacology     Volume:  228     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  1992 Sep 
Date Detail:
Created Date:  1992-12-24     Completed Date:  1992-12-24     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  77-83     Citation Subset:  IM    
Department of Nephrology, G. Gaslini Institute, Genoa, Italy.
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MeSH Terms
Adenosine Deaminase / metabolism
Cell Survival / drug effects
Cells, Cultured
Doxorubicin / toxicity*
Kidney Glomerulus / drug effects*,  enzymology,  metabolism
Methionine / metabolism
Rats, Sprague-Dawley
Superoxides / metabolism
Thymidine / metabolism
Xanthine Oxidase / metabolism
Reg. No./Substance:
11062-77-4/Superoxides; 23214-92-8/Doxorubicin; 50-89-5/Thymidine; 63-68-3/Methionine; EC Oxidase; EC Deaminase

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