Document Detail


Mechanisms of the deleterious effects of tamoxifen on mitochondrial respiration rate and phosphorylation efficiency.
MedLine Citation:
PMID:  11714246     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tamoxifen (TAM), the widely prescribed drug in the prevention and therapy of breast cancer, is a well-known modulator of estrogen receptor (ER) that also inhibits the proliferation of different cell types that lack the ER. However, the ER-independent action mechanisms of TAM and its side effects have not been yet clarified. Mitochondria are essential in supporting the energy-dependent regulation of cell functions. Changes in mitochondria result in bioenergetic deficits leading to the loss of vital functions to cell survival. Therefore, this study describes the effects of TAM on mitochondrial bioenergetics, contributing to a better understanding of the biochemical mechanisms underlying the multiple antiproliferative and toxic effects of this drug. TAM at concentrations above 20 nmol/mg protein, preincubated with isolated rat liver mitochondria at 25 degrees C for 3 min, significantly depresses, in a dose-dependent manner, the phosphorylation efficiency of mitochondria as inferred from the decrease in the respiratory control and ADP/O ratios, the perturbations in mitochondrial transmembrane potential (DeltaPsi), the fluctuations associated with mitochondrial energization, and the phosphorylative cycle induced by ADP. Furthermore, TAM at up to 40 nmol/mg protein stimulates the rate of state 4 respiration and at higher concentrations it strongly inhibits state 3 and uncouples the mitochondrial respiration. The stimulation of state 4 respiration parallels the decrease of DeltaPsi as a consequence of proton permeability. The TAM-stimulatory action of ATPase is also observed in intact mitochondria, suggesting that TAM promotes extensive permeability to protons due to destructive effects in the structural integrity of the mitochondrial inner membrane. These multiple effects of TAM on mitochondrial bioenergetic functions, causing changes in the respiration, phosphorylation efficiency, and membrane structure, may explain the cell death induced by this drug in different cell types, its anticancer activity in ER-negative cells, and its side effects.
Authors:
C M Cardoso; J B Custódio; L M Almeida; A J Moreno
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  176     ISSN:  0041-008X     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2001 Nov 
Date Detail:
Created Date:  2001-11-20     Completed Date:  2001-12-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  145-52     Citation Subset:  IM    
Copyright Information:
Copyright 2001 Academic Press.
Affiliation:
Laboratório de Bioquímica, Universidade de Coimbra, Coimbra, Portugal.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Diphosphate / analysis,  pharmacology
Adenosine Triphosphatases / metabolism
Animals
Antineoplastic Agents, Hormonal / pharmacology
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
Energy Metabolism / drug effects
Membrane Potentials / drug effects
Mitochondria, Liver / chemistry,  drug effects*,  metabolism*
Oxygen / analysis
Oxygen Consumption / drug effects*
Phosphorylation
Rats
Rats, Wistar
Tamoxifen / pharmacology*
Uncoupling Agents / pharmacology
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Hormonal; 0/Uncoupling Agents; 10540-29-1/Tamoxifen; 370-86-5/Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; 58-64-0/Adenosine Diphosphate; 7782-44-7/Oxygen; EC 3.6.1.-/Adenosine Triphosphatases

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


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