AC Swart Group
GROUP LEADER: Prof. AC Swart
Position: Emeritus Professor
Office: A120 JC Smuts Building
Phone: +27-(0)21-808-5864
Fax: +27-(0)21-808-5863
Email: acswart@sun.ac.za
Educational Background
PhD, 中国体育彩票 of Stellenbosch, 1999
Research Emphasis
Adrenal steroidogenesis, cytochrome P450 enzymes, prostate cancer, and natural plant products: Aspalatus linearis (Rooibos), Salsola tuberculatiformis Botch. (Gannabos) and Sutherlandia frutescens (Cancer bush).
Research Focus
Adrenal steroidogenesis, cytochrome P450 enzymes, prostate cancer, and natural plant products: Aspalatus linearis (Rooibos), Salsola tuberculatiformis Botch. (Gannabos) and Sutherlandia frutescens (Cancer bush).
Our primary focus is on adrenal steroidogenesis – on the hormones produced by the adrenal gland as well as on the steroidogenic enzymes which catalyse their biosynthesis. Stemming from this interest are our investigations into (i) the downstream metabolism of adrenal C19 steroids in prostate cancer and (ii) the biosynthesis and downstream metabolism of adrenal steroids implicated in endocrine disorders. Adrenal steroidogenic pathways are studied by the heterologous expression of enzymes, together with investigations into the metabolism of steroids in adrenal and prostate cell models. These metabolic pathways also form the basis of our ongoing studies into the biological activities of natural plant products and their influence on the human endocrine system.?
Research Proje?cts
The biosynthesis and metabolism of 11β-hydroxyandrostenedione (11OHA4)
11OHA4 is a unique adrenal C19 steroid, the hydroxylation of which is catalysed by CYP11B1 and B2. This steroid, together with 11hydroxy-testosterone (11OHT) is metabolized to more active androgens in prostate cells, yielding 11hydroxy-5α-dione and 11keto-5α-dione as well as 11hydroxy-dihydrotestosterone (11OHDHT) and 11keto-dihydrotestosterone (11KDHT). Our investigations include the metabolism, inactivation and conjugation of adrenal androgens in prostate cancer cell models as well as in normal cancer cells. Our studies have implicated 11OHA4 in prostate cancer and in its progression to castration resistant prostate cancer (CRPC).
11OHA4 and 11hydroxy-testosterone (11OHT) together with their 11keto-derivatives pose novel substrates for 11β-hydroxysteroid dehydrogenase (11βHSD) type1 and type2. Since 11βHSD has been shown to be present in LNCaP cells, an androgen dependent prostate cancer cell line, we are defining the role of these isoforms in prostate cancer and in CRPC. 11βHSD may furthermore also have a role to play in endocrine disorders and disease conditions characterized by CYP21A2 deficiency resulting in the high levels of these and other C11-oxygenated adrenal steroids.
These studies are supported by the National Research Foundation (NRF)
The influence of Rooibos on ??androgen metabolism in prostate cancer
We are investigating the modulatory role of Rooibos in the production of active androgens. Rooibos decreases adrenal androgen production in the H295R adrenal cell model and inhibits key steroidogenic enzymes, cytochrome P450 17A1 and 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2), in the androgen biosynthesis pathway. In prostate cell models, Rooibos's inhibition of 17β-hydroxysteroid dehydrogenases (17βHSD) is comparable to that of indomethacin, a 17βHSD5 inhibitor, resulting in decreased T production. While 17βHSD was inhibited in LNCaP, PC-3 cells and in benign prostatic hyperplasia (BPH) cells, 5α-reductase (SRD5A) was not. Further investigations include determining the effect of Rooibos on PSA levels, a prostate cancer marker and on the inactivation of active androgens.
These studies are supported by the Cancer Association of South Africa (CANSA).
?The influence of Rooibos? on cortisol and stress
The ongoing studies into the adrenal steroidogenic P450 enzymes include investigations into the inhibition of these enzymes by natural plant products. Our investigations into plant products, some of which act as natural inhibitors of the P450 enzymes may well contribute towards our understanding of the structure/function relationship of the mammalian steroidogenic enzymes as well as the influence of natural plant products on the human endocrine system.
We have shown that Rooibos modulates adrenal hormone production, decreasing cortisol production in H295R cells while also inhibiting 11βHSD type 1, possibly accounting for the decreased cortisol:cortisone ratios in humans consuming Rooibos. Our investigations have been extended to include the immune modulating properties of Rooibos.
These studies are supported by the South African Rooibos Council (SARC).?
Selected Publications
?Schloms, L., Storbeck, K-H., Swart, P., Gelderblom, W.C.A. and Swart, A.C. 2012. The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells. Journal of Steroid Biochemistry and Molecular Biology 128, 128–138.
Swart, A.C., Schloms, L., Storbeck, K-H., Bloem, LM., du Toit, T., Quanson, J.L., Rainey, W.E. and Swart, P. (2013) 11β-Hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-Hydroxy-5α-androstanedione Journal of Steroid Biochemistry and Molecular Biology 138, 132– 142.
Storbeck, K-H., Bloem, L.M., Africander, D., Schloms, L., Swart, P. and Swart, A.C. (2013) Adrenal 11beta-hydroxyandrostenedione is metabolised to novel androgenic dihydrotestosterone derivatives, 11-ketodihydrotestosterone and 11-hydroxydihydrotestosterone in androgen-dependent LNCaP cells. Molecular and Cellular Endocrinology 377 135–146
Bloem, L.M., Storbeck, K-H., Schloms, L., and Swart, A.C. (2013) 11β-hydroxyandrostenedione returns to the steroid arena: biosynthesis, metabolism and function. Molecules. 18, 13228-13244.
Schloms, L., Smith C., Storbeck, K-H., Swart, P., Marnewick,J.L. and Swart, A.C. (2014). Rooibos influences glucocorticoid levels and steroid ratios in vivo and in vitro: a natural approach in the management of stress and metabolic disorders? Molecular Nutrition and Food Research. 2014, 58, 537–549.
Schloms, L and Swart, A.C. (2014) Rooibos flavonoids inhibit the activity of key adrenal steroidogenic enzymes, modulating steroid hormone levels in H295R cells. Molecules. 19(3), 3681-3695;
Swart, A.C. and Storbeck, K-H. (2015) 11β-hydroxyandrostenedione: downstream metabolism by 11βHSD, 17βHSD and SRD5A - novel substrates in familiar pathways. Molecular and Cellular Endocrinology. In Press
Bloem, LM., Storbeck, K-H., Swart, P., du Toit, T., Schloms, L. and Swart, A.C. (2015). Advances in the analytical methodologies: profiling steroids in familiar pathways –challenging dogmas. Journal of Steroid Biochemistry and Molecular Biology. In Press??
