Lipophilic oestrogen derivatives contained in lipoprotein particles.

Steroid fatty acid esters constitute a unique family of lipophilic hormones carried exclusively in circulating lipoproteins. Our studies have focused on the formation of 17beta fatty acid esters of labelled oestradiol in in vitro incubations with human ovarian follicular fluid and plasma and demonstrated the accumulation of these labelled derivatives in lipoprotein particles. The oestradiol esters are formed in a reaction catalysed by lecithin : cholesterol acyltransferase in association with high-density lipoprotein particles and they can be transferred to low-density lipoprotein particles in a process mediated by cholesteryl ester transfer protein. Using a novel quantitative method for the determination of oestradiol esters their endogenous concentrations in follicular fluid and in early and late pregnancy plasma have been determined. In addition, using labelled genistein and its chemically synthesized fatty acid esters, we also demonstrated that phytoestrogen derivatives could be incorporated in lipoprotein particles. Both oestradiol and genistein contain aromatic hydroxyl groups which cause them to exert powerful antioxidant activity in lipid-aqueous systems in vitro. The physiological role of the steroidal fatty acid esters remains to be elucidated. In theory, the hormonal esters might form a reservoir constituted by esterified hormones stored in lipoprotein particles and perhaps in fat tissue, or they might use lipoproteins as vehicles for endocrine transport, or they could act as antioxidant protection of the lipoprotein particles. Enzyme systems necessary for the formation of lipophilic oestrogen and phytoestrogen derivatives as well as for their incorporation in lipoprotein particles are present in human body fluids. Because of their water-insolubility, steroid fatty acid esters are carried exclusively by circulating lipoproteins. These esters can provide antioxidant protection for lipoprotein particles.

Accumulation of high-density lipoprotein-derived estradiol-17beta fatty acid esters in low-density lipoprotein particles.

Estrogens are known to be powerful antioxidants in lipid-aqueous systems, as demonstrated by their inhibition of low-density lipoprotein (LDL) oxidation in vitro. Studies reporting that endogenous human estrogens could be rendered fat-soluble by esterification with fatty acids in vivo, and the subsequent detection of such esters in blood and fat tissue suggested a possible mechanism explaining how estrogens might protect LDL. Because of their lipophilicity, esterified estrogens may become incorporated in the lipoprotein structure, providing antioxidant potential for the particles. We incubated labeled 17beta-estradiol with ovarian follicular fluid and with plasma in the absence and presence of the LCAT inhibitor DTNB. This was followed by ultracentrifugal isolation of LDL and high-density lipoprotein and analysis of the radioactive label in the "ester" and "free" fractions purified from these lipoproteins. The results indicated that LCAT-mediated synthesis of esterified 17beta-estradiol occurred in high-density lipoprotein particles, and suggested a novel cholesterol ester transfer protein-mediated mechanism for their transfer to LDL particles.

Antioxidant protection of lipoproteins containing estrogens: in vitro evidence for low- and high-density lipoproteins as estrogen carriers.

Some recent studies have reported that low-density lipoprotein (LDL) isolated from estrogen-treated postmenopausal women exhibited increased oxidation resistance ex vivo. However, the underlying mechanisms responsible for this effect are not clear. We explored the possibility that lipophilic derivatives of 17beta-estradiol (E(2)) could be incorporated into LDL and high-density lipoprotein (HDL) particles inhibiting lipoprotein oxidation. Introduction of small amounts of esterified E(2) into lipoproteins by means of incubation of free E(2) and E(2) 17-stearate in plasma did not result in any antioxidant effect. Using an artificial transfer system (Celite dispersion), larger amounts of E(2) esters could be incorporated into lipoproteins. Concentrations ranging between 0.27 and 1.38 molecules/LDL particle for E(2) 17-stearate and between 0.36 and 1.93 molecules/LDL particle for E(2) 17-oleate resulted in increased Cu(2+)-induced oxidation resistance of LDL as indicated by statistically significant lag time prolongations. Significant prolongations of lag times were also observed for HDL following incorporation of E(2) esters using Celite as transfer system. Our results suggest that free E(2) can be esterified and incorporated into lipoproteins during incubation in plasma. However, incorporation of supraphysiologic concentrations of E(2) esters into lipoproteins by means of the artificial transfer system was required in order to reduce their oxidation susceptibility.