THE EFFECT OF THE ANTICANCER DRUGS TAMOXIFEN AND HYDROXYTAMOXIFEN ON THE CALCIUM-PUMP OF ISOLATED SARCOPLASMIC-RETICULUM VESICLES

The interactions of tamoxifen (TAM) and its active metabolite 4-hydrox ytamoxifen (OHTAM) with the sarcoplasmic reticulum (SR) Ca2+-pump were investigated. The turnover of the Ca2+-ATPase is strongly inhibited b y both drugs at low concentrations that do not significantly perturb t he lipid organization of SR membranes. Moreover, TAM decreases Ca2+ ac cumulation by SR Ca2+-ATPase and increases in parallel the ATP hydroly sis, decreasing the energetic efficiency of the Ca2+-pump (Ca2+/ATP co upling ratio) by about 70% at 30 mu M. This uncoupling of ATP hydrolys is from Ca2+ accumulation is a putative consequence of structural defe cts 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 TA M, it inhibits ATP hydrolysis. Thus, the Ca2+/ATP ratio is decreased b y about 47% at 30 mu M OHTAM; this effect is not a consequence of memb rane disruption, since the ATP-splitting activity decreases in paralle l to Ca2+ accumulation and no significant effect is detected for ATP h ydrolysis at low residual Ca2+. The inhibition of the Ca2+-pump by OHT AM is putatively related to a direct interaction with the regulatory s ites of the enzyme or interactive perturbations at the lipid-protein i nterface. The effect may result from a decrease of efficiency in the e nergy transmission and transduction between the ATP use at the catalyt ic site and the channeling process involved in Ca2+ translocation. The refore, the effects of the drugs on the Ca2+-pump are different and ru le out an unitary mechanism of action on the basis of bilayer structur e perturbations. Copyright (C) 1996 Elsevier Science Ltd.