Browsing Department of Biochemistry by browse.metadata.advisor "Arlt, Wiebke"
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- ItemAn investigation into the biosynthesis, metabolism and activity of 11-oxygenated estrogens(Stellenbosch : Stellenbosch University, 2020-04) Barnard, Lise; Storbeck, Karl-Heinz; Arlt, Wiebke; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.ENGLISH ABSTRACT: Within recent years, a growing number of studies have implicated 11-oxygenated androgens as important role players in women’s health. Significantly, 11-ketotestosterone (11KT) circulates at levels equal to or greater than that of testosterone (T) in healthy women, with elevated levels observed in patients with polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH). Given that androgens are obligatory precursors to produce estrogens, a conversion catalysed by cytochrome P450 aromatase (aromatase), it is important to consider whether 11-oxygenated androgens can be aromatized into a corresponding group of 11-oxygenated estrogens. This study shows for the first time that 11-oxygenated androgens are indeed substrates for aromatase leading to the production of 11-oxygenated estrogens, a novel group of bioactive estrogens not previously considered in human physiology. Using several aromatase expressing systems, we also show that 11-oxygenated estrogens can be produced from the aromatase catalysed 11β-hydroxylation of classic estrogens, a reaction never before reported for this enzyme. We go on to show that the 11-oxygenated estrogen, 11β-hydroxyestradiol (11OHE2), binds to and activates both subtypes of the human estrogen receptor (ERα and ERβ), stimulates ER-dependent proliferation and upregulates ER-regulated gene expression in estrogen sensitive breast cancer cell lines. In addition, this study investigated the metabolism of 11KT by steroid 5α-reductase isozymes (SRD5A1 and SRD5A2), and steroid 5β-reductases (AKR1D1). We show for the first time that AKR1D1 catalyses the inactivation of 11KT committing its metabolism to a pathway that feeds into the production of the urinary steroid 11-ketoetiocholanolone (11KEt), which has to date only been considered a metabolite of the abundant glucocorticoid, cortisone. Collectively, this study provides valuable insights into the metabolism of 11-oxygenated androgens. The identification of a novel class of 11-oxygenated estrogens further challenges long-established dogmas in the field of endocrinology and shows that the contribution of the 11-oxygenated androgens, and by extension, 11-oxygenated estrogens, can no longer be disregarded.