| Cellular targets of 3'-azido-3'-deoxythymidine: an early (non-delayed) effect on oxidative phosphorylation. | |
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MedLine Citation:
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PMID: 7646539 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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G A Hobbs; S A Keilbaugh; P M Rief; M V Simpson |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Biochemical pharmacology Volume: 50 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 1995 Jul |
Date Detail:
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Created Date: 1995-09-19 Completed Date: 1995-09-19 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 381-90 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Cell Biology, State University of New York, Stony Brook 11794, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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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:
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AI29905/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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