Antioxidant and prooxidant actions of estrogens: potential physiological and clinical implications

Oxidative stress and free radical-mediated cell death have been linked to diseases such as atherosclerosis, Alzheimer's disease, and cancer. Estrogens may promote, or offer protection against these conditions, by acting both as an antioxidant and prooxidant. Estrogens are converted to catecholestrogens via an oxidation step. Catecholestrogens are precursors of quinones that undergo a reversible oxidation-reduction reaction yielding semiquinones and reactive oxygen species. These semiquinones and reactive oxygen species may act as prooxidants and result in DNA and protein damage that may play a role in initiating tumor growth. Estrogen may also stimulate the peroxidase reaction, thereby promoting prooxidant reactions catalyzed by estrogen. Such reactions may be involved in enhancing the oxidizability of low-density lipoproteins (LDL). This mechanism of oxidation of LDL in plasma may actually lead to increased clearance of LDL by the liver and thereby contribute to estrogens' antiatherogenic action. On the other hand, participation of catecholestrogens in iron redox cycling may contribute to the antioxidant action of estrogens. This action might be important in sites such as the subendothelial space where estrogens are thought to inhibit LDL oxidation. Estrogens may also exert antioxidant effects by acting on genes with response elements for antioxidants. This may in turn inhibit expression of certain proteins involved in disease processes such as atherogenesis. Thus, by acting as an antioxidant and prooxidant, estrogen may produce both beneficial and adverse effects important in the prevention and pathogenesis of disease.