Custódio J B, Dinis T C, Almeida L M, Madeira V M
Laboratório de Bioquímica, Faculdade de Farmácia, Universidade de Coimbra, Portugal.
Biochem Pharmacol. 1994 Jun 1;47(11):1989-98. doi: 10.1016/0006-2952(94)90073-6.
Tamoxifen (TAM) is the antiestrogen most widely used in the chemotherapy and chemoprevention of breast cancer. It has been reported that TAM and its more active metabolite 4-hydroxytamoxifen (OHTAM) induce multiple cellular effects, including antioxidant actions. Here sarcoplasmic reticulum membranes (SR) were used as a simple model of oxidation to clarify the antioxidant action type and mechanisms of these anticancer drugs on lipid peroxidation induced by Fe2+/ascorbate and peroxyl radicals generated by the water-soluble 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH) and by the lipid-soluble 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN). Peroxidation was monitored by different assay systems, namely cis-parinaric acid (PnA) fluorescence quenching, production of thiobarbituric acid-reactive substances, polyunsaturated fatty acids (PUFA) degradation and oxygen consumption. TAM and OHTAM are efficient inhibitors of lipid peroxidation induced by Fe2+/ascorbate and strong intramembraneous scavengers of peroxyl radicals generated either in the water or lipid phases by AAPH and AMVN, respectively. However, these drugs are not typical chain-breaking antioxidant compounds as compared with vitamin E. Additionally, their antioxidant effectiveness enhances the protective capacity of vitamin E against lipid peroxidation induced by AMVN. OHTAM is a more powerful intramembraneous inhibitor of lipid peroxidation as compared with TAM; this effectiveness not correlating with alterations on membrane fluidity may be due to the presence of a hydrogen-donating HO-group in the OHTAM molecule and its preferential location in the outer bilayer regions where it can donate the hydrogen atom to quench free radicals capable of initiating the membrane oxidative degradation. The stronger OHTAM intramembraneous scavenger capacity over TAM also correlates with its higher partition in biomembranes. Therefore, the strong peroxyl radical scavenger activity of OHTAM in the hydrophobic membrane phase may putatively contribute to the mechanisms of cytostatic and chemopreventive action of its promoter TAM on development of breast cancer.
他莫昔芬（TAM）是乳腺癌化疗和化学预防中使用最广泛的抗雌激素药物。据报道，TAM及其活性更高的代谢物4-羟基他莫昔芬（OHTAM）可诱导多种细胞效应，包括抗氧化作用。在此，肌浆网膜（SR）被用作一个简单的氧化模型，以阐明这些抗癌药物对由Fe2+/抗坏血酸诱导的脂质过氧化以及由水溶性2,2'-偶氮二异丁脒二盐酸盐（AAPH）和脂溶性2,2'-偶氮二（2,4-二甲基戊腈）（AMVN）产生的过氧自由基的抗氧化作用类型和机制。通过不同的检测系统监测过氧化反应，即顺式-紫黄质（PnA）荧光猝灭、硫代巴比妥酸反应性物质的产生、多不饱和脂肪酸（PUFA）降解和氧气消耗。TAM和OHTAM分别是Fe2+/抗坏血酸诱导的脂质过氧化的有效抑制剂，以及AAPH和AMVN在水相和脂相产生的过氧自由基的强膜内清除剂。然而，与维生素E相比，这些药物不是典型的链断裂抗氧化化合物。此外，它们的抗氧化效果增强了维生素E对AMVN诱导的脂质过氧化的保护能力。与TAM相比，OHTAM是一种更强有力的膜内脂质过氧化抑制剂；这种有效性与膜流动性的改变无关，可能是由于OHTAM分子中存在供氢的羟基基团，且其优先位于外双层区域，在该区域它可以提供氢原子以淬灭能够引发膜氧化降解的自由基。OHTAM比TAM更强的膜内清除剂能力也与其在生物膜中的更高分配相关。因此，OHTAM在疏水膜相中的强过氧自由基清除活性可能推测有助于其母体TAM对乳腺癌发展的细胞生长抑制和化学预防作用机制。
