Raloxifene is a better antioxidant of low-density lipoprotein than estradiol or tamoxifen in postmenopausal women in vitro.
OBJECTIVE
The oxidation of low-density lipoprotein (LDL) is an important factor in the development of atherosclerosis. The antioxidant activity of some compounds buffers the free radicals generated either endogenously or exogenously, thus decreasing the potential damage mediated by oxidation. Estrogens are potent antioxidants of LDL, in vitro and in vivo, a mechanism that could probably influence the cardioprotection associated with hormone replacement therapy in postmenopause. We conducted an in vitro study of the antioxidant effect on LDL of two selective estrogen receptor modulators, raloxifene (RLX) and tamoxifen (TMX), comparing them with the known antioxidant effect of estradiol (E2 ).


METHODS
LDL was isolated by ultracentrifugation from plasma obtained from 12 healthy, untreated, postmenopausal women. Aliquots containing 0.5 mg of LDL protein were incubated for 4 h with CuSO4 (15 micro M) to induce oxidative stress and with one of the three compounds studied: RLX, TMX, or E2 at doses of 0, 1, 2, 3, 5, 15, 50, and 500 micro M, and 1 and 2 mM. Malonaldehyde (MDA, nmol/mg protein) was measured as a marker of LDL oxidation.


RESULTS
E2 induced a dose-dependent decrease in MDA concentration. MDA values decreased significantly, as compared with baseline, starting at a concentration of 2 micro M for RLX and 3 micro M for both, TMX, or E2. The dose necessary to reduce the generation of MDA by 50% was significantly lower for RLX (3.3 micro M, < 0.001) than for E2 (24.6 micro M ) or TMX (35.3 micro M). The area under the curve also showed a higher antioxidant activity for RLX compared with TMX or E2 ( < 0.001).


CONCLUSIONS
The in vitro antioxidant activity of RLX is substantially more potent than TMX or E2. This finding, added to the other beneficial effects of the drug in the cardiovascular system, could imply some cardioprotector effect.
Arteaga
Eugenio
E
Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago Chile. arteaga@med.puc.cl
Villaseca
Paulina
P
Bianchi
Marcelo
M
Rojas
Auristela
A
Marshall
Guillermo
G
D000975:Antioxidants / Q000494:pharmacology*; D019540:Area Under Curve; D001161:Arteriosclerosis / Q000517:prevention & control; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008315:Malondialdehyde / Q000378:metabolism; D008875:Middle Aged; D017698:Postmenopause; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology
D000975:Antioxidants; D008078:Cholesterol, LDL; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D008315:Malondialdehyde