Doctoral Degrees (Biochemistry)

Permanent URI for this collection

https://scholar.sun.ac.za/handle/10019.1/3909

Browse

Browsing Doctoral Degrees (Biochemistry) by Subject "Adrenal androgens"

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    The metabolism of 11β-hydroxyandrostenedione by steroidogenic enzymes yields metabolites contributing to the androgen pool in prostate cancer
    (Stellenbosch : Stellenbosch University, 2018-03) Du Toit, Therina; Swart, Amanda C.; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.
    ENGLISH ABSTRACT: This study describes: • The development and validation of three ultra-performance convergence chromatography tandem mass spectrometry (UPC2-MS/MS) analytical methods which were applied in the detection and quantification of C19 and C21 steroids, including C11-oxy C19 and C11-oxy C21 steroids; • The investigation into the contribution of adrenal 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT) to the pool of active androgens in the prostate, by following androgen metabolism in normal epithelial prostate PNT2, benign prostatic hyperplasia (BPH-1) and prostate cancer LNCaP, C4-2B and VCaP cell models; Steroid profiles revealed 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) activity in all the cell models, confirmed in the conversion of 11OHA4 to 11keto-androstenedione (11KA4), with reductive 17β-hydroxysteroid dehydrogenase (17βHSD) enzymes metabolising 11KA4, ultimately yielding 11keto-testosterone (11KT). • The in vitro investigation into the inactivation, reactivation, glucuronidation and sulfation of 11OHA4, 11OHT and their downstream metabolites; In prostate cancer (PCa) cell models, the conjugation of 11KT and 11ketodihydrotestosterone (11KDHT) were hampered compared to testosterone (T) and dihydrotestosterone (DHT), while the inactivation and reactivation of the C11-oxy C19 steroids were less efficient than the C19 steroids in BPH-1 cells. • The in vivo steroid profiles in PCa, BPH and castration-resistant prostate cancer (CRPC) tissue and plasma of healthy and PCa patients; Analyses of the C19 and C11-oxy C19 steroids, together with glucuronide and sulfate conjugates, showed increased unconjugated levels of 11KT and 11KDHT in plasma of PCa patients compared to a healthy subject, and 11OHA4, 11KT and 11KDHT levels were prominent in PCa tissue, while downstream inactive C11-oxy 3α-reduced metabolites were identified in BPH and CRPC tissue.