Hydroxytamoxifen protects against oxidative stress in brain mitochondria

Abstract

This study evaluated the effect of hydroxytamoxifen, the major active metabolite of tamoxifen (synthetic, nonsteroidal antiestrogen drug), on the function of brain mitochondria. We observed that only high concentrations of hydroxytamoxifen (60 nmol/mg protein) induced a significant decrease in RCR, while ADP/O ratio remained statistically unchanged. Similarly, only the highest concentration of hydroxytamoxifen (60 nmol/mg protein) affected the phosphorylative capacity of brain mitochondria, characterized by a decrease in the repolarization level and an increase in the repolarization lag phase. We observed that all the concentrations of hydroxytamoxifen tested (7.5, 15 and 30 nmol/mg protein) prevented lipid peroxidation induced by the oxidant pair ADP/Fe 2þ . Furthermore, through the analyses of calcium fluxes and mitochondrial transmembrane potential parameters, we observed that hydroxytamoxifen (30 nmol/mg protein) exerted some protection against pore opening, although in a less extension than that promoted by cyclosporin A, the specific inhibitor of the mitochondrial permeability transition pore. However, in the presence of hydroxytamoxifen plus cyclosporin A, the protection observed was significantly higher when compared with that induced by both agents alone.These results support the idea that hydroxytamoxifen protects lipid peroxidation and inhibits the mitochondrial permeability transition pore in brain. Since numerous neurodegenerative diseases are intimately related with mitochondrial dysfunction resulting from lipid peroxidation and induction of mitochondrial permeability transition, among other factors, future therapeutical strategies could be designed taking in account this neuroprotective role of hydroxytamoxifen, which is pharmacologically much more potent and less toxic than its promoter tamoxifen. #

Doxorubicin increases the susceptibility of brain mitochondria to Ca2+-induced permeability transition and oxidative damage

“…Previously, Zhou et al [35] showed that the decrease in Ca 2+ loading capacity promoted by DOX treatment is not reversed over a 5-week period after the discontinuation of the treatment, suggesting that the alteration of mitochondrial Ca 2+ regulation induced by DOX is persistent and irreversible. In accordance with previous studies, preincubation of mitochondria with oligomycin plus ADP or CsA, the inhibitors of PTP, significantly increased the capacity of mitochondria to accumulate Ca 2+ [6,[39][40][41]. It is known that the PTP is potentiated upon the oxidation of protein thiol groups in the pore complex [42].…”

Estradiol affects liver mitochondrial function in ovariectomized and tamoxifen-treated ovariectomized female rats

“…2 and 3). Accordingly, previous in vitro studies also indicate that TAM (Custodio et al, 1998;Moreira et al, 2005) and OHTAM (Cardoso et al, 2002;Moreira et al, 2004) are potent inhibitors of PTP induction in liver and brain mitochondria. However, we observed that E2 exposure does not interfere with Ca 2+ influx (Fig.…”

“…Therefore, changes in the structural and functional characteristics of mitochondria provide a number of primary targets for drugs-induced toxicity and cell death (Wallace and Starkov, 2000). Indeed, accumulating evidence indicates that both 17β-estradiol (E2) (Zheng and Ramirez, 1999;Yang et al, 2004) and TAM (Custodio et al, 1998;Moreira et al, 2004Moreira et al, ,2005) modulate mitochondrial function.…”

Neuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity

“…Tamoxifen, or its immediate metabolite 4-hydroxytamoxifen, are effective antioxidants (Dubey et al, 1999;Wiseman et al, 1994), and antioxidants have been clearly shown to be protective in brain trauma and stroke (Hall et al, 1989;Chan, 1999). The major tamoxifen metabolite, 4-OH tamoxifen was shown to markedly reduce induced lipid peroxidation in brain mitochondria in vitro (Moreira et al, 2004), but the antioxidative effects of tamoxifen have never been directly tested in stroke models. During ischemia and especially during reperfusion there are high levels of free radicals generated, which would be expected to attack proteins and lipids of the cell membrane and mitochondria.…”