Document Detail


Cellular targets of 3'-azido-3'-deoxythymidine: an early (non-delayed) effect on oxidative phosphorylation.
MedLine Citation:
PMID:  7646539     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Previous results demonstrated that incubation of the Friend murine erythroleukemic cell with 5 microM AZT for several days leads to a decrease in the rate of cell growth, inhibition of mtDNA replication, reduction of mtDNA per cell and per mitochondrion, and an increase in mitochondria per cell. As shown here, such treatment also leads to changes in lactate and ATP synthesis and in O2 uptake, suggesting impairment of oxidative phosphorylation. Direct measurement of ATP synthesis in mitochondria isolated from AZT-treated cells confirmed this view. The most significant new finding in this paper, however, is that in addition to these delayed effects of AZT, similar but very rapidly appearing effects on oxidative phosphorylation were noted, with changes observed in the above parameters including mitochondrial proliferation. Some of these occurred as early as 3 hr, only 7% of the doubling time, after exposure of the cells to 5 microM AZT, a period too short for initiation of appreciable mtDNA-mediated effects. Studies on isolated mitochondria provided no evidence of the identity of the immediate target of AZT: AZT does not act as an uncoupler or inhibitor of respiratory control, and previous results failed to implicate adenylate kinase. We have also begun to address the question of the mechanism of AZT-induced mitochondrial proliferation. Initial experiments showed that AZT inhibited synthesis of total cytosolic protein but stimulated synthesis of those proteins imported into mitochondria from the cytoplasm. We also report that aminothymidine, a catabolite of AZT in liver capable of inhibiting cell growth, was not generated by Friend cells.
Authors:
G A Hobbs; S A Keilbaugh; P M Rief; M V Simpson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  50     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  1995 Jul 
Date Detail:
Created Date:  1995-09-19     Completed Date:  1995-09-19     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  381-90     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Cell Biology, State University of New York, Stony Brook 11794, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Animals
Cell Division / drug effects
Cell Line
Cytosol / drug effects
DNA Replication / drug effects
DNA, Mitochondrial / drug effects
Dideoxynucleosides / metabolism
Lactates / metabolism
Lactic Acid
Mice
Mitochondria / drug effects*,  metabolism
Oxidative Phosphorylation / drug effects*
Oxygen / metabolism
Protein Biosynthesis
Time Factors
Zidovudine / pharmacology*
Grant Support
ID/Acronym/Agency:
AI29905/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial; 0/Dideoxynucleosides; 0/Lactates; 30516-87-1/Zidovudine; 50-21-5/Lactic Acid; 52450-18-7/3'-aminothymidine; 56-65-5/Adenosine Triphosphate; 7782-44-7/Oxygen

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


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