Tamoxifen and hydroxytamoxifen as intramembraneous inhibitors of lipid peroxidation. Evidence for peroxyl radical scavenging activity.
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.
Laboratório de Bioquímica, Faculdade de Farmácia, Universidade de Coimbra, Portugal.
J B
JB
Custódio
T C
TC
Dinis
L M
LM
Almeida
V M
VM
Madeira
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001391:Azo Compounds / Q000494:pharmacology; D005296:Ferrous Compounds / Q000494:pharmacology; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide / Q000737:chemistry; D007425:Intracellular Membranes / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D010101:Oxygen Consumption; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors
D000578:Amidines; D001391:Azo Compounds; D005296:Ferrous Compounds; D016166:Free Radical Scavengers; D009570:Nitriles; C051140:iron(II)-ascorbic acid complex; C055792:2,2'-azobis(2,4-dimethylvaleronitrile); D013629:Tamoxifen; C016601:afimoxifene; C046728:2,2'-azobis(2-amidinopropane); D006861:Hydrogen Peroxide; D001205:Ascorbic Acid