TAMOXIFEN AND HYDROXYTAMOXIFEN AS INTRAMEMBRANOUS INHIBITORS OF LIPID-PEROXIDATION - EVIDENCE FOR PEROXYL RADICAL SCAVENGING ACTIVITY

Tamoxifen (TAM) is the antiestrogen most widely used in the chemothera py and chemoprevention of breast cancer. It has been reported that TAM and its more active metabolite 4-hydroxytamoxifen (OHTAM) induce mult iple cellular effects, including antioxidant actions. Here sarcoplasmi c reticulum membranes (SR) were used as a simple model of oxidation to clarify the antioxidant action type and mechanisms of these anticance r drugs on lipid peroxidation induced by Fe2+/ascorbate and peroxyl ra dicals generated by the water-soluble 2,2'-azobis(2-amidinopropane)dih ydrochloride (AAPH) and by the lipid-soluble 2,2'-azobis(2,4-dimethylv aleronitrile) (AMVN). Peroxidation was monitored by different assay sy stems, namely cis-parinaric acid (PnA) fluorescence quenching, product ion of thiobarbituric acid-reactive substances, polyunsaturated fatty acids (PUFA) degradation and oxygen consumption. TAM and OHTAM are eff icient inhibitors of lipid peroxidation induced by Fe2+/ascorbate and strong intramembraneous scavengers of peroxyl radicals generated eithe r 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 peroxidat ion induced by AMVN. OHTAM is a more powerful intramembraneous inhibit or of lipid peroxidation as compared with TAM; this effectiveness not correlating with alterations on membrane fluidity may be due to the pr esence of a hydrogen-donating HO-group in the OHTAM molecule and its p referential location in the outer bilayer regions where it can donate the hydrogen atom to quench free radicals capable of initiating the me mbrane oxidative degradation. The stronger OHTAM intramembraneous scav enger capacity over TAM also correlates with its higher partition in b iomembranes. Therefore, the strong peroxyl radical scavenger activity of OHTAM in the hydrophobic membrane phase may putatively contribute t o the mechanisms of cytostatic and chemopreventive action of its promo ter TAM on development of breast cancer.