Amanda C Swart

Amanda C Swart
Stellenbosch University, Stellenbosch · Biochemistry

36.38
 · 
PhD

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101
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Publications

Publications (101)
Article
Full-text available
The metabolism of 11β-hydroxyandrostenedione (11OHA4), a major adrenal C19 steroid, was first characterised in our in vitro prostate models showing that 11OHA4, catalysed by 11βHSDs, 17βHSDs and 5α-reductases, yields potent androgens, 11keto-testosterone (11KT) and 11keto-dihydrotestosterone (11KDHT) in the 11OHA4-pathway [1]. Findings have since l...
Article
Background: We recently identified 35 women with polycystic ovarian syndrome (PCOS) who exhibited features of micronodular adrenocortical hyperplasia. Steroid hormone analysis can be more accurate using state-of-the-art ultra-performance convergence chromatography-tandem mass spectrometry (UPC2-MS/MS). We hypothesized that UPC2-MS/MS may be used t...
Article
Full-text available
Obtaining longitudinal endocrinological data from free-ranging animals remains challenging. Steroid hormones can be extracted sequentially from non-invasively sampled biologically inert keratinous tissues, such as feathers, nails, hair and whiskers. However, uncertainty regarding the type and levels of steroids incorporated into such tissues compli...
Article
Full-text available
Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) plays a pivotal role in the regulation of adrenal and gonadal steroid hormone biosynthesis. More recent studies highlighted the enzyme's role in the backdoor pathway leading to androgen production. Increased CYP17A1 activity in endocrine disorders and diseases are associated with elevated C21 an...
Article
Full-text available
In clinical approaches to benign prostatic hyperplasia (BPH) and prostate cancer (PCa), steroidogenesis or the disruption thereof is the main thrust in treatments restricting active androgen production. Extensive studies have been undertaken focusing on testosterone and dihydrotestosterone (DHT). However, the adrenal C11-oxy C19 steroid, 11β-hydrox...
Article
The C11-oxy C21 steroids, 11αOHP4 (11α-hydroxyprogesterone) and 11βOHP4 (11β-hydroxyprogesterone), have to date been characterised only in terms of their inhibition of 11β-hydroxysteroid dehydrogenase (11βHSD). However, 11βOHP4 is also a substrate of 11βHSD2 and is converted to 11-ketoprogesterone which is subsequently metabolised to active C11-oxy...
Article
Adrenal steroid hormones have been implicated in numerous clinical conditions with adrenal androgens marked as major contributors in the progression of androgen-dependent diseases and disorders such as congenital adrenal hyperplasia, 21-hydroxylase deficiency, polycystic ovary syndrome (PCOS) and castration-resistant prostate cancer. Although adren...
Article
Adrenal C19 steroids, testosterone and androstenedione, have long been the only androgens considered contributing to clinical conditions characterised by androgen excess. More recently, we showed that adrenal 11β-hydroxyandrostenedione is converted to 11-ketotestosterone and 11-ketodihydrotestosterone (11KDHT), both activating the androgen receptor...
Article
Full-text available
Objective: This study is a post-hoc analysis of steroid hormones before and after administration of pharmacological doses of soy isoflavones in a large cohort of men and women from two independent studies. Isoflavones are reported to inhibit mineralo- and glucocorticoid hormone production as well as reproductive steroids in vivo and in vitro. We fo...
Article
Full-text available
11α-Hydroxyprogesterone (11αOHP4)and 11β-hydroxyprogesterone (11βOHP4)have been reported to be inhibitors of 11β-hydroxysteroid dehydrogenase (11βHSD)type 2, together with 11β-hydroxytestosterone and 11β-hydroxyandrostenedione, and their C11-keto derivatives being inhibitors of 11βHSD1. Our in vitro assays in transiently transfected HEK293 cells, h...
Article
The 11β-hydroxysteroid dehydrogenase (11βHSD) types 1 and 2 are primarily associated with glucocorticoid inactivation and reactivation. Several adrenal C11-oxy C 19 and C11-oxy C 21 steroids, which have been identified in prostate cancer, 21-hydroxylase deficiency and polycystic ovary syndrome, are substrates for these isozymes. This study describe...
Article
Increasing consumer bias toward natural products and the considerable wealth of indigenous knowledge has precipitated an upturn in market-driven research into potentially beneficial medicinal plants. In this context, Aspalathus linearis (Rooibos) has been identified to be a promising candidate which may impact cardiovascular disease (CVD), which is...
Article
The purpose of this study was to identify the C11-oxy C19 and C11-oxy C21 steroids in male and female neonate plasma. At birth, the most abundant C11-oxy steroids detected in neonatal plasma were 11β-hydroxyandrostenedione, ∼13 nM, and 11-ketoprogesterone, ∼23 nM. C11-oxy C19 steroids were higher than C19 steroids in neonatal plasma, 22.2 nM vs 5.4...
Article
Increased circulating 11β-hydroxyprogesterone (11OHP4), biosynthesised in the human adrenal, is associated with 21-hydroxylase deficiency in congenital adrenal hyperplasia. 17α-hydroxyprogesterone levels are also increased, with the steroid's metabolism to dihydrotestosterone in the backdoor pathway contributing to hyperandrogenic clinical conditio...
Article
The incidence of skin cancer, resulting from exposure to UVB irradiation, has become a global concern as it continues to rise rapidly with the non-melanoma skin cancers, comprised of basal cell carcinoma and squamous cell carcinoma, being the most frequently diagnosed in Caucasian populations. Chronic inflammation is suggested to contribute to canc...
Article
Although the adrenal C19 steroids, androstenedione and testosterone, contribute to prostate cancer (PCa) progression the full complement of adrenal androgens, including the C11-oxy C19 steroids, 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT) and their androgenic metabolites, 11keto-testosterone (11 KT) and 11keto-dihydrotes...
Article
21-Hydroxylase deficiency presents with increased levels of cytochrome P450 21‐hydroxylase substrates, progesterone and 17α-hydroxyprogesterone, which have been implicated in the production of androgens via the backdoor pathway. This study shows the biosynthesis of C11-oxy C21 steroids, 21‐deoxycortisol and 21-deoxycortisone, and their metabolism b...
Article
Ethnopharmacological relevance: Sutherlandia frutescens is a traditional African medicinal plant used in the treatment of stress and anxiety, while also exhibiting anti-inflammatory properties. Aim of study: The study aimed at linking anti-stress and anti-inflammatory properties of S. frutescens to its influence on glucocorticoid biosynthesis and t...
Article
Ethnopharmacological relevance: Sutherlandia frutescens is a traditional African medicinal plant used in the treatment of stress and anxiety, while also exhibiting anti-inflammatory properties. Aim of study: The study aimed at linking anti-stress and anti-inflammatory properties of S. frutescens to its influence on glucocorticoid biosynthesis an...
Article
The maintenance of steroid homeostasis in the prostate is critical, with perturbation of steroidogenesis contributing to the modulation of active ligands in the androgen pool. In this scenario, enzymes catalysing the biosynthesis, inactivation and conjugation of steroids are the key players, regulating active ligand levels and in so doing, the acti...
Article
16α-hydroxyprogesterone (16OHP4) is not well characterised in terms of metabolism and receptor interaction. We therefore investigated its metabolism by adrenal CYP11B and peripheral steroidogenic enzymes, SRD5A and AKR1C2. UHPLC-MS/MS analyses identified novel steroids: the biosynthesis of 4-pregnen-11β,16α-diol-3,20-dione catalysed by CYP11B2; the...
Article
Full-text available
Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids...
Article
Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids...
Article
Cytochrome b5 (cyt-b5) is a relatively small haemoprotein which plays an important role in the regulation of mammalian steroidogenesis. This unique protein has the ability to modulate the activity of key steroidogenic enzymes via a number of diverse reaction mechanisms. Cyt-b5 can augment the 17,20-lyase activity of CYP17A1 by promoting the interac...
Conference Paper
Interleukin-1α is a primary cytokine that is constitutively produced by keratinocytes in skin where it facilitates cell proliferation and inflammation [1–3] . The chronic production of this cytokine, however, is associated with skin cancer development. Plant compounds have been shown to prevent chronic inflammation and cancer development in skin by...
Article
To determine the effect of Rooibos (Aspalathus linearis) on glucocorticoid biosynthesis and inactivation in vivo and in vitro. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) analyses of in vivo studies showed that human Rooibos consumption increased cortisone plasma levels in males (p = 0.0465) and reduced cortisol:co...
Article
Major rooibos flavonoids-dihydrochalcones, aspalathin and nothofagin, flavones-orientin and vitexin, and a flavonol, rutin, were investigated to determine their influence on the activity of adrenal steroidogenic enzymes, 3β-hydroxysteroid dehydrogenase (3βHSD2) and cytochrome P450 (P450) enzymes, P450 17α-hydroxylase/17,20-lyase (CYP17A1), P450 21-...
Article
The biological significance of 11β-hydroxyandrostenedione (11OHA4) has eluded researchers for the past six decades. It is now known that 11OHA4 is biosynthesized in the androgen arm of the adrenal steroidogenesis pathway and subsequently metabolized by steroidogenic enzymes in vitro, serving as precursor to recognized and novel androgenic steroids....
Article
Adrenal C19 steroids, dehydroepiandrostenedione (DHEA(S)) and androstenedione (A4), play a critical role in castration-resistant prostate cancer (CRPC) as they are metabolised to dihydrotestosterone (DHT), via testosterone (T), or via the alternate 5α-dione pathway, bypassing T. Adrenal 11OHA4 metabolism in CRPC is, however, unknown. We present a n...
Article
11β-hydroxyandrostenedione (11OHA4), which is unique to the adrenal, was first isolated from human adrenal tissue in the fifties. It was later shown in the sixties that 11β-hydroxytestosterone (11OHT) was also produced by the human adrenal. Attention has shifted back to these adrenal androgens once more, as detection methods have enabled more accur...
Article
Full-text available
In commercial production systems, the full expression of an animal's genetic potential is limited by its intrinsic and extrinsic environment. It is therefore necessary to include robustness as a breeding goal, because robustness is defined as the ability of an animal to express a high production potential in a wide variety of environmental conditio...
Article
Cytochrome b(5) (cyt-b(5)) is essential for the regulation of steroidogenesis and as such has been implicated in a number of clinical conditions. It is well documented that this small hemoprotein augments the 17,20-lyase activity of cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1). Studies have revealed that this augmentation is accomplished b...
Article
The biosynthesis of steroid hormones, essential to the survival of all mammals, is dependent on the activity of 3β-hydroxysteroid dehydrogenase/Δ(5)-Δ(4) isomerase (3βHSD). 3βHSD activity is, in turn, influenced by cytochrome-b(5) (Cyt-b(5)). However, the mechanism through which this occurs is unknown. In this study, we investigated this mechanism...
Article
Cytochrome b(5) (cyt-b(5)) is a ubiquitous hemoprotein also associated with microsomal cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17A1). In the steroidogenic pathway CYP17A1 catalyses the metabolism of pregnenolone, yielding both glucocorticoid and androgen precursors. While not affecting the 17α-hydroxylation of pregnenolone, cyt-b(5) augment...
Article
During adrenal steroidogenesis the competition between 3β-hydroxysteroid dehydrogenase/Δ(5)-Δ(4) isomerase (3βHSD) and cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17A1) for Δ(5) steroid intermediates greatly influences steroidogenic output. Cytochrome-b(5) (Cyt-b(5)), a small electron transfer hemoprotein, known to augment the lyase activity of...
Article
The metabolism of progesterone (PROG) by cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) results in the formation of both 17α-hydroxyprogesterone (17-OHPROG) and 16α-hydroxyprogesterone (16-OHPROG) in humans. Unlike 17-OHPROG, 16-OHPROG is not metabolised further in steroidogenic tissue. While this metabolite can be readily detected in serum...
Article
In adrenal steroidogenesis, CYP17 catalyses the 17α-hydroxylation of pregnenolone and progesterone and the subsequent 17,20-lyase reaction, yielding adrenal androgens. The enzyme exhibits distinctly different selectivities towards these substrates in various species. CYP17 has also been shown to exhibit 16α-hydroxylase activity towards progesterone...
Article
South African Angora goats are susceptible to cold stress, due to their inability to produce sufficient levels of cortisol. During adrenal steroidogenesis the production of cortisol relies on the activity of two key enzymes, namely cytochrome P450 17α-hydroxylase and 3β-hydroxysteroid dehydrogenase. Cytochrome P450 17α-hydroxylase has previously be...
Article
Two cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17) isoforms have been identified in the South African Angora goat (Capra hircus) and have been implicated as the primary cause of hypocortisolism in this subspecies. These goats are the most efficient fibre producing, but least hardy, small stock breed in Southern Africa. Their inability to c...
Article
In mammals, cytochrome P450 17alpha-hydroxylase/17-20 lyase (CYP17), which is encoded by a single gene, plays a critical role in the production of mineralocorticoids, glucocorticoids and androgens by the adrenal cortex. Two CYP17 isoforms with unique catalytic properties have been identified in the South African Angora goat (Capra hircus), a subspe...
Article
The aim of this study was to investigate whether Sutherlandia frutescens, subsp. microphylla (family: Fabaceae/Leguminosa), which is traditionally used to treat symptoms of chronic stress generally associated with increased circulating glucocorticoids, influences the biosynthesis of these glucocorticoids. We investigated the interaction of Sutherla...
Article
An ultra performance liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (UPLC-APCI-MS) method was developed for the separation and quantification of adrenal steroid metabolites from heterologous expression media. Steroids were extracted by liquid-liquid extraction, separated on a Waters UPLC BEH C18 column, ionized by...
Article
Human cytochrome P45017alpha (CYP17), present in mammalian adrenal and gonadal tissues, catalyses both steroid 17-hydroxylation and C17,20 lyase reactions, producing intermediates for the glucocorticoid and androgenic pathways, respectively. The characterisation of this complex enzyme was initially hampered due to low level in vivo expression of CY...
Article
Cytochrome P450 side-chain cleavage (CYP11A1) catalyzes the conversion of cholesterol to pregnenolone, the first step in steroidogenesis. The absence of a solved crystal structure has complicated deductions pertaining to the structure/function relationships of this key enzyme. Although a number of techniques have been employed to identify domains a...
Article
Full-text available
South African Angora goats (Capra hircus) are susceptible to cold stress, due to the inability of the adrenal cortex to produce sufficient levels of cortisol. Two CYP17 isoforms were identified, cloned and characterized in this study. Sequence analysis revealed three amino acid differences between the two CYP17 isoforms, which resulted in a signifi...
Article
To gain further insight into the structure/function relationship of cytochrome P450 side-chain cleavage (CYP11A1), this enzyme was investigated in the Cape baboon (Papio ursinus). Four constructs were cloned and characterised in non-steroidogenic mammalian COS-1 cells. Wild type recombinant baboon CYP11A1 cDNA yielded a K(m) value of 1.6 microM for...
Article
Sutherlandia frutescens (Cancer bush), a Southern African indigenous plant, is traditionally used to treat stress related maladies linked to the endocrine system. Extracts of the shrub were used to investigate the claimed stress-relieving properties of the shrub. Dysregulation of the stress response is associated with elevated glucocorticoid levels...
Article
Cytochrome P450 side-chain cleavage (CYP11A1) catalyzes the first and "rate-limiting" step in steroidogenesis, the conversion of cholesterol to pregnenolone. In an effort to gain further insight into the structure/function relationship of this key enzyme, CYP11A1 was characterized in the Cape baboon (Papio ursinus), a species closely related to hum...
Article
Plants belonging to the genus Salsola (Family: Chenopodiaceae) are common in the arid and semiarid regions of our planet with no less than 69 different Salsola species found in Namibia and the Republic of South Africa. This genus is used as a traditional medicine and aqueous extracts of Salsola have been used by Bushmen women as an oral contracepti...
Article
The steroid 17-hydroxylase cytochrome P450 (CYP17) found in mammalian adrenal and gonadal tissues typically exhibits not only steroid 17-hydroxylase activity but also C-17,20-lyase activity. These two reactions, catalyzed by CYP17, allow for the biosynthesis of the glucocorticoids in the adrenal cortex, as a result of the 17-hydroxylase activity, a...
Article
A third gene encoding baboon CYP11B1 was isolated and was shown to catalyze only the metabolism of deoxycorticosterone (DOC) to corticosterone. The investigation into the localization of CYP11B1 in the baboon adrenal tissue, using in situ hybridization, showed that mRNA transcripts were predominantly present in the zona reticularis (ZR) and zona fa...
Article
Cytochrome b5 (cyt b5) is an ubiquitous hemoprotein also associated with microsomal cytochromes P450. It has been reported that cyt b5 influences cytochrome P450-dependent catalyses through electron transport as well as direct protein-protein interactions. To investigate the influence of cyt b5 on ovine adrenal steroidogenesis, we isolated and char...
Article
Human cytochrome P450 17α-hydroxylase (CYP17) catalyses not only the 17α-hydroxlation of pregnenolone and progesterone and the C17,20-side chain cleavage (lyase) of 17α-hydroxypregnenolone, necessary for the biosynthesis of C21-glucocorticoids and C19-androgens, but also catalyses the 16α-hydroxylation of progesterone. In efforts to understand the...
Article
Cytochrome b(5) (cyt b(5)) is an ubiquitous hemoprotein also associated with microsomal cytochromes P450. It has been reported that cyt b(5) influences cytochrome P450-dependent catalyses through electron transport as well as direct protein-protein interactions. To investigate the influence of cyt b(5) on ovine adrenal steroidogenesis, we isolated...