Evidence for interference in estradiol-17 beta inactivation to estrone by oxidized low-density lipoprotein and selected lipid peroxidation products

An elevation in plasma estrogen levels is believed to play a key role in th e pathogenesis of breast cancer. The conversion of estradiol-17 beta (E2) t o estrone (E1) by 17 beta-hydroxy steroid dehydrogenase type 4 (17-HSD4) re presents a major pathway of its inactivation in cells. In this study the po tential relationship between lipoprotein peroxidation products and E2 metab olism was examined. It was noted that oxidized low-density lipoprotein (OX- LDL), not native LDL, caused a time- and concentration-dependent inhibition of the conversion of labeled E2 to E1 in THP-1 macrophage cells. Further s tudies noted that among the lipoprotein peroxidation products examined, mal ondialdehyde (MDA) caused a marked decrease in this reaction, whereas hexan al and a variety of oxysterols had no effect. This inhibition of E1 formati on from E2 in THP-1 cells was confirmed by the quantitation of estrone form ed with high-pressure liquid chromatography and by the expression of 17-HSD 4 by reverse transcriptase-polymerase chain reaction. MDA added to Hep G2 c ells showed a similar trend in E1 formation. These results suggest that inc reased oxidative stress and lipid peroxidation might result in decreased in activation of biologically active estrogen. This might be important in post menopausal women undergoing estrogen replacement therapy.