Estrogen-Mediated Breast Carcinogenesis: The Role of Sulfation Pharmacogenetics
Abstract
The carcinogenic effects of estrogen as a result of receptor-mediated mechanisms are well established. However, a growing body of evidence suggests that estrogens may also be direct genotoxins. Specifically, the catecholestrogens (CEs), 2- hydroxyestrone (2-OHEl), 2-hydroxyestradiol (2-OHE2), 4- hydroxyestrone (4-OHEl) and 4-hydroxyestradiol (4-OHE2) are estrogen metabolites that can be metabolically activated to semiquinones and quinones and form stable and depurinating DNA adducts. The depurinating DNA adducts are formed from 4- OHEl and 4-OHE2 and they result in mutations that lead to genotoxicity and therefore breast carcinogenesis. Prevention of the genotoxic effects of these estrogen metabolites can be achieved in part through the sulfate-conjugation of the CEs, catalyzed by Sulfotransferase (SULT) enzymes. Many of the human cytosolic SULTs are genetically polymorphic, thus, inherited differences in the activities of these enzymes may contribute to the pathophysiology of breast cancer. As such, we determined the activity of 13 recombinant human SULTs with both 4-OHEl and 4-OHE2, and also with the other CEs, 2-OHEl and 2-OHE2 and the parent estrogens, estrone (El) and l7-beta-% estradiol (E2). All but one of the SULTs studied catalyzed these reactions to varying degrees. SULT lEl had the highest affinity for the CEs, with apparent Km values of 0.31 and 0.18 uM for 4-OHEl and 4-OHE2 respectively. These results suggest that any individual variation in the sulfate conjugation of CEs catalyzed by SULTs may represent a risk factor for breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2000
- Accession Number
- ADB264903
Entities
People
- Araba Adjei