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Titolo:
THE EFFECT OF THE ANTICANCER DRUGS TAMOXIFEN AND HYDROXYTAMOXIFEN ON THE CALCIUM-PUMP OF ISOLATED SARCOPLASMIC-RETICULUM VESICLES
Autore:
CUSTODIO JBA; ALMEIDA LM; MADEIRA VMC;
Indirizzi:
UNIV COIMBRA,FAC FARM,LAB BIOQUIM,COURACA APOSTOLOS NO 51 R-C P-3000 COIMBRA PORTUGAL UNIV COIMBRA,CTR NEUROCIENCIAS P-3049 COIMBRA PORTUGAL
Titolo Testata:
Toxicology in vitro
fascicolo: 5, volume: 10, anno: 1996,
pagine: 523 - 531
SICI:
0887-2333(1996)10:5<523:TEOTAD>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-C; BREAST-CANCER; TRANSMEMBRANE CHANNEL; LIPID-PEROXIDATION; MEMBRANE FLUIDITY; ESTROGEN-RECEPTOR; CA2+ TRANSPORT; CA-2+ EFFLUX; INHIBITION; BINDING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
54
Recensione:
Indirizzi per estratti:
Citazione:
J.B.A. Custodio et al., "THE EFFECT OF THE ANTICANCER DRUGS TAMOXIFEN AND HYDROXYTAMOXIFEN ON THE CALCIUM-PUMP OF ISOLATED SARCOPLASMIC-RETICULUM VESICLES", Toxicology in vitro, 10(5), 1996, pp. 523-531

Abstract

The interactions of tamoxifen (TAM) and its active metabolite 4-hydroxytamoxifen (OHTAM) with the sarcoplasmic reticulum (SR) Ca2+-pump were investigated. The turnover of the Ca2+-ATPase is strongly inhibited by both drugs at low concentrations that do not significantly perturb the lipid organization of SR membranes. Moreover, TAM decreases Ca2+ accumulation by SR Ca2+-ATPase and increases in parallel the ATP hydrolysis, decreasing the energetic efficiency of the Ca2+-pump (Ca2+/ATP coupling ratio) by about 70% at 30 mu M. This uncoupling of ATP hydrolysis from Ca2+ accumulation is a putative consequence of structural defects induced on membranes, since the ATP hydrolysis at low residual Ca2+ (Ca2+ not supplemented) is also stimulated. On the other hand, OHTAM decreases the Ca2+ uptake to a greater extent than TAM but, unlike TAM, it inhibits ATP hydrolysis. Thus, the Ca2+/ATP ratio is decreased by about 47% at 30 mu M OHTAM; this effect is not a consequence of membrane disruption, since the ATP-splitting activity decreases in parallel to Ca2+ accumulation and no significant effect is detected for ATP hydrolysis at low residual Ca2+. The inhibition of the Ca2+-pump by OHTAM is putatively related to a direct interaction with the regulatory sites of the enzyme or interactive perturbations at the lipid-protein interface. The effect may result from a decrease of efficiency in the energy transmission and transduction between the ATP use at the catalytic site and the channeling process involved in Ca2+ translocation. Therefore, the effects of the drugs on the Ca2+-pump are different and rule out an unitary mechanism of action on the basis of bilayer structure perturbations. Copyright (C) 1996 Elsevier Science Ltd.

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Documento generato il 09/07/20 alle ore 17:47:54