Antioxidant protection of LDL by physiological concentrations of 17 beta-estradiol. Requirement for estradiol modification.
BACKGROUND
Exposure to estrogens reduces the risk for coronary artery disease and associated clinical events; however, the mechanisms responsible for these observations are not clear. Supraphysiological levels of estrogens act as antioxidants in vitro, limiting oxidation of low-density lipoprotein (LDL), an event implicated in atherogenesis. We investigated the conditions under which physiological concentrations of 17 beta-estradiol (E2) inhibit oxidative modification of LDL.


RESULTS
Plasma incubated with E2 (0.1 to 100 nmol/L) for 4 hours yielded LDL that demonstrated a dose-related increase in resistance to oxidation by Cu2+ as measured by conjugated diene formation. This effect was dependent on plasma, because incubation of isolated LDL with E2 at these concentrations in buffered saline produced no effect on Cu(2+)-mediated oxidation. Incubation of plasma with E2 had no effect on LDL alpha-tocopherol content or cholesteryl ester hydroperoxide formation during the 4-hour incubation. Plasma incubation with [3H]E2 was associated with dose-dependent association of 3H with LDL. High-performance liquid chromatographic analysis of LDL derived from plasma incubated with [3H]E2 indicated that the majority of the associated species were not detectable as authentic E2 but as nonpolar forms of E2 that were susceptible to base hydrolysis consistent with fatty acid esterification of E2. Plasma-mediated association of E2 and subsequent antioxidant protection was inhibited by 5,5'-dithiobis(2-nitrobenzoic acid), an inhibitor of plasma acyltransferase activity.


CONCLUSIONS
Exposure of LDL to physiological levels of E2 in a plasma milieu is associated with enhanced resistance to Cu(2+)-mediated oxidation and incorporation of E2 derivatives into LDL. This antioxidant capacity may be another means by which E2 limits coronary artery disease in women.
Shwaery
G T
GT
Evans Memorial Department of Medicine, Boston University Medical Center, MA 02118, USA.
Vita
J A
JA
Keaney
J F
JF
D000578:Amidines / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism; D004136:Dinitrobenzenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004951:Esterification; D004958:Estradiol / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D013997:Time Factors; D014810:Vitamin E / Q000494:pharmacology
D000578:Amidines; D000975:Antioxidants; D004136:Dinitrobenzenes; D008077:Lipoproteins, LDL; D014810:Vitamin E; D004958:Estradiol; C046728:2,2'-azobis(2-amidinopropane); D003300:Copper; C010936:2,4-dinitrothiocyanatobenzene