Uptake and protection against oxidative stress by estrogen esters in THP-1 human macrophage cell lines

Estrogen replacement therapy offers protection from coronary artery disease in postmenopausal women. However, there is serious concern that long-term unopposed estrogen use increases the risk of breast and endometrial cancer through estrogen-receptor-driven mechanisms. In this communication, we have explored an alternate route of estrogen delivery to macrophages using hydrophobic derivatives that associate with lipoproteins. Unlike free estradiol (E(2)), long-chain fatty acid esters of E(2) associate extensively with low-density lipoprotein (LDL). In THP-1 cells, E(2) esters accumulated to a significantly higher level when compared to E(2) in the presence of LDL. In the presence of oxidized LDL even greater amounts of E(2) esters accumulated in cells. In THP-1 cells, E(2) esters were capable of preventing the azo-bis-induced increase in oxidative stress (hydrogen peroxide formation). These studies suggest that (a) hydrophobic esters of estrogens that associate with LDL can be delivered to macrophages and (b) these esters can effectively function as antioxidants protecting against oxidative stress.