The effects of 4-hydroxytamoxifen (OHTAM), the major active metabolite of the antiestrogen tamoxifen used in the breast cancer therapy, were studied on the mitochondrial permeability transition (MPT) and bioenergetic functions of mitochondria to evaluate the mechanisms underlying the cell death and toxic effects. The MPT was induced in vitro by incubating rat liver mitochondria with 1 mM inorganic phosphate plus Ca2+ and with tert-butyl hydroperoxide. OHTAM provides protection against the Ca2+-induced mitochondrial swelling, depolarization of the mitochondrial membrane potential (deltapsi), loss of electrophoretic Ca2+ uptake capacity and uncoupling of respiration, similarly to cyclosporine A. The concentrations of OHTAM used do not significantly affect deltapsi, respiratory control and adenosine diphosphate/oxygen ratios and induce repolarization and Ca2+ re-uptake, suggesting that such inhibitory effects of OHTAM were due to the prevention of the MPT induction and not due to the inhibition of the mitochondrial Ca2+ uniporter. Since the MPT induction has been linked to an oxidized shift in the mitochondrial redox state and/or increase in the generation of reactive oxygen species, the MPT prevention by OHTAM may be related to its high antioxidant capacity.

中文翻译：

---

4-Hydroxytamoxifen 是一种有效的线粒体通透性转变抑制剂

研究了 4-羟基三苯氧胺 (OHTAM)（用于乳腺癌治疗的抗雌激素三苯氧胺的主要活性代谢物）对线粒体通透性转变 (MPT) 和生物能功能的影响，以评估细胞死亡和毒性的潜在机制。效果。通过将大鼠肝线粒体与 1 mM 无机磷酸盐加 Ca2+ 和叔丁基过氧化氢一起在体外诱导 MPT。OHTAM 提供针对 Ca2+ 诱导的线粒体肿胀、线粒体膜电位 (deltapsi) 去极化、电泳 Ca2+ 吸收能力丧失和呼吸解偶联的保护，类似于环孢菌素 A。使用的 OHTAM 浓度不会显着影响 deltapsi，呼吸控制和二磷酸腺苷/氧比并诱导复极化和 Ca2+ 再摄取，表明 OHTAM 的这种抑制作用是由于阻止了 MPT 诱导，而不是由于抑制了线粒体 Ca2+ 单向转运蛋白。由于 MPT 诱导与线粒体氧化还原状态的氧化转变和/或活性氧产生的增加有关，因此 OHTAM 对 MPT 的预防可能与其高抗氧化能力有关。