scholarly journals Selective Inhibition of Steroidogenic Enzymes by Ketoconazole in Rat Ovary Cells

2014 ◽  
Vol 8 ◽  
pp. CMRH.S14036 ◽  
Author(s):  
Michael Gal ◽  
Joseph Orly
Keyword(s):  
Selective Inhibition ◽  
Hydroxysteroid Dehydrogenase ◽  
Dependent Manner ◽  
Steroidogenic Enzymes ◽  
Ovary Cells ◽  
Estrogen Synthesis ◽  
Lyase Activity ◽  
Testicular Steroidogenesis ◽  
Rat Ovary

Objective Ketoconazole (KCZ) is an anti-fungal agent extensively used for clinical applications related to its inhibitory effects on adrenal and testicular steroidogenesis. Much less information is available on the effects of KCZ on synthesis of steroid hormones in the ovary. The present study aimed to characterize the in situ effects of KCZ on steroidogenic enzymes in primary rat ovary cells. Methods Following the induction of folliculogenesis in gonadotropin treated rats, freshly prepared ovarian cells were incubated in suspension for up to four hours while radiolabeled steroid substrates were added and time dependent generation of their metabolic products was analyzed by thin layer chromatography (TLC). Results KCZ inhibits the P450 steroidogenic enzymes in a selective and dose dependent manner, including cholesterol side-chain cleavage cytochrome P450 (CYP11A1/P450scc), the 17α-hydroxylase activity of CYP17A1/P450c17, and CYP19A1/P450arom, with IC50 values of 0.3, 1.8, and 0.3 μg/mL (0.56, 3.36, and 0.56 μM), respectively. Unaffected by KCZ, at 10 μg/mL, were the 17,20 lyase activity of CYP17A1, as well as five non-cytochrome steroidogenic enzymes including 3β-hydroxysteroid dehydrogenase-δ5-4 isomerase type 1 (3βHSD1), 5α-reductase, 20α-hydroxysteroid dehydrogenase (20α-HSD), 3α-hydroxysteroid dehydrogenase (3α-HSD), and 17β-hydroxysteroid dehydrogenase type 1 (17HSD1). Conclusion These findings map the effects of KCZ on the ovarian pathways of progestin, androgen, and estrogen synthesis. Hence, the drug may have a potential use as an acute and reversible modulator of ovarian steroidogenesis in pathological circumstances.

scholarly journals Expression of Key Androgen-Activating Enzymes in Ovarian Steroid Cell Tumor, Not Otherwise Specified

2020 ◽  
Vol 8 ◽  
pp. 232470962093341
Author(s):  
Evana Valenzuela Scheker ◽  
Amita Kathuria ◽  
Ashwini Esnakula ◽  
Hironobu Sasano ◽  
Yuto Yamazaki ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Steroidogenic Enzymes ◽  
Androgen Excess ◽  
Ovarian Steroid ◽  
Variable Expression ◽  
Not Otherwise Specified ◽  
Chain Cleavage ◽  
Cleavage Enzyme

To characterize the expression of steroidogenic enzymes implicated in the development of ovarian steroid cell tumors, not otherwise specified (SCT-NOS). We present 4 ovarian SCT-NOS evaluated by immunohistochemical staining of steroidogenic enzymes as an approach to define this entity pathologically. All 4 ovarian SCT-NOS showed increased expression for cholesterol side-chain cleavage enzyme (CYP11A1), 17α-hydroxylase (CYP17A1), 17β-hydroxysteroid dehydrogenase 1 (HSD17B1), aldo-ketoreductase type 1 C3 (AKR1C3), 3β-hydroxysteroid dehydrogenase 2 (HSD3B2), 5α-reductase type 2 (SRD5A2), steroid sulfatase (SULT2A1), estrogen sulfotransferase (EST), and aromatase (CYP19A1). Expression was negative for 21-hydroxylase (CYP21A2) and 17β-hydroxysteroid dehydrogenase 2 (HSD17B2). 17β-hydroxysteroid dehydrogenase 3 (HSD17B3) and 5α-reductase type 1 (SRD5A1) showed variable expression. Our analysis reveals a novel finding of increased expression of AKR1C3, HSD17B1, SRD5A2, SULT2A1, and EST in ovarian SCT-NOS, which is clinically associated with androgen excess and virilization. Further studies are needed to validate these enzymes as new markers in the evaluation of hyperandrogenic ovarian conditions.

Studies on the effect of prolactin treatment on testicular steroidogenesis and gametogenesis in lithium-treated rats

1991 ◽  
Vol 125 (3) ◽  
pp. 313-318 ◽  
Author(s):  
D. Ghosh ◽  
N. M. Biswas ◽  
P. K. Ghosh
Keyword(s):  
Lithium Chloride ◽  
Lithium Treatment ◽  
Serum Levels ◽  
Hydroxysteroid Dehydrogenase ◽  
Significant Inhibition ◽  
Steroidogenic Enzymes ◽  
Subcutaneous Injections ◽  
Testicular Dysfunction ◽  
Testicular Steroidogenesis ◽  
Chloride Treatment

Abstract. The effect of PRL supplementation in lithium-treated rats on spermatogenesis, testicular Δ5-3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase activities, and serum levels of FSH, LH, PRL and testosterone were studied on the 22nd day of the experiment. Subcutaneous injections of lithium chloride at a dose of 2.0 mg·kg−1·day−1 for 21 days resulted in a significant inhibition of spermatogenesis at stage VII of the seminiferous epithelial cycle, along with remarkable diminution of serum levels of the above hormones and suppression of the activities of the above two testicular steroidogenic enzymes. Administration of bovine PRL at a dose of 0.25 mg·kg−1·day−1 plus lithium treatment resulted in a remarkable protection of spermatogenic and steroidogenic activities of the testes, along with restoration of serum levels of FSH and testosterone. It is concluded that PRL can markedly protect the testicular dysfunction induced by lithium chloride treatment in rats.

Rat 17 beta-hydroxysteroid dehydrogenase type 1: primary structure and regulation of enzyme expression in rat ovary by diethylstilbestrol and gonadotropins in vivo.

Endocrinology ◽  
1994 ◽  
Vol 135 (4) ◽  
pp. 1477-1487 ◽  
Author(s):  
S Ghersevich ◽  
P Nokelainen ◽  
M Poutanen ◽  
M Orava ◽  
H Autio-Harmainen ◽  
...  
Keyword(s):  
Primary Structure ◽  
Hydroxysteroid Dehydrogenase ◽  
Enzyme Expression ◽  
Rat Ovary

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome

2013 ◽  
Vol 15 (2) ◽  
Author(s):  
Roland H. Stimson ◽  
Brian R. Walker
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Selective Inhibition ◽  
Hydroxysteroid Dehydrogenase ◽  
The Metabolic Syndrome ◽  
Specific Regulation ◽  
Visceral Adipose ◽  
Subcutaneous Adipose

AbstractThe cortisol regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels, particularly in the liver and adipose tissue. The importance of this enzyme in causing metabolic disease was highlighted by transgenic mice which over- or under-expressed 11β-HSD1; consequently, selective 11β-HSD1 inhibitors have been widely developed as novel agents to treat obesity and type 2 diabetes mellitus (T2DM). This review focuses on the importance of 11β-HSD1 in humans which has been more difficult to ascertain. The recent development of a deuterated cortisol tracer has allowed us to quantify in vivo cortisol production by 11β-HSD1. These results have been surprising, as cortisol production rates by 11β-HSD1 are at least equivalent to that of the adrenal glands. The vast majority of this production is by the liver (>90%) with a smaller contribution from subcutaneous adipose tissue and possibly skeletal muscle, but with no detectable production from visceral adipose tissue. This tracer has also allowed us to quantify the tissue-specific regulation of 11β-HSD1 observed in obesity and obesity-associated T2DM, determine the likely basis for this dysregulation, and identify obese patients with T2DM as the group most likely to benefit from selective inhibition of 11β-HSD1. Some of these inhibitors have now reached Phase II clinical development, demonstrating efficacy in the treatment of T2DM. We review these results and discuss whether selective 11β-HSD1 inhibitors are likely to be an important new therapy for metabolic disease.

scholarly journals Effects of polychlorinated biphenyl (Aroclor 1254) on steroidogenesis and antioxidant system in cultured adult rat Leydig cells

2007 ◽  
Vol 192 (2) ◽  
pp. 325-338 ◽  
Author(s):  
Palaniappan Murugesan ◽  
Muthusamy Balaganesh ◽  
Karundevi Balasubramanian ◽  
Jagadeesan Arunakaran
Keyword(s):  
Antioxidant System ◽  
Leydig Cells ◽  
Hydroxysteroid Dehydrogenase ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Steroidogenic Enzymes ◽  
Aroclor 1254 ◽  
Nonenzymatic Antioxidants ◽  
Dose Dependent

Polychlorinated biphenyls (PCBs) are ubiquitous and persistent environmental contaminants that disturb normal endocrine functions, including gonadal functions in humans and mammals. In the present study, we examined the direct effects of PCB on rat Leydig cells in vitro. Adult Leydig cells were purified by Percoll gradient centrifugation method and the purity of Leydig cells was also determined by 3β-hydroxysteroid dehydrogenase (3β-HSD) staining method. Purified Leydig cells were exposed to different concentrations (10− 10–10− 7 M) of PCB (Aroclor 1254) for 24 h under basal and LH-stimulated conditions. After the experimental period, cultured media were collected and used for the assay of testosterone and estradiol. The treated cells were used for the quantification of cell-surface LH receptors and activities of steroidogenic enzymes, such as cytochrome P450 side-chain cleavage enzyme (P450scc), 3β-HSD, and 17β-hydroxysteroid dehydrogenase (17β-HSD). Leydig cellular enzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, γ-glutamyl transpeptidase, glutathione-S-transferase, and nonenzymatic antioxidants, such as vitamins C and E, were assayed. Lipid peroxidation (LPO) and reactive oxygen species (ROS) were also estimated in Leydig cells. In addition, total RNA was isolated from control and Aroclor 1254-exposed Leydig cells to monitor the steady-state mRNA levels by reverse transcription(RT)-PCR for steroidogenic acute-regulatory (StAR) protein, cytochrome P450scc, 3β-HSD, and 17β-HSD. Our results indicated that Aroclor 1254 (10− 9, 10− 8, and 10− 7 M) treatments significantly inhibit basal and LH-stimulated testosterone and estradiol production. In addition, the activities of steroidogenic enzymes, enzymatic and nonenzymatic antioxidants were significantly diminished in a dose-dependent manner. However, LPO and ROS were elevated in a dose-dependent manner under basal and LH-stimulated conditions. RT-PCR analysis of StAR mRNA level showed a decrease only in 10− 7 M dose of Aroclor 1254 treatment, while cytochrome P450scc, 3β-HSD, and 17β-HSD mRNAs were drastically decreased in both 10− 8 and 10− 7 M Aroclor 1254 treatment. These findings suggest that PCBs can act directly on Leydig cells to diminish testosterone production by inhibiting gene expression of steroidogenic enzymes and antioxidant system.

scholarly journals Selective Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Improves Hepatic Insulin Sensitivity in Hyperglycemic Mice Strains

Endocrinology ◽  
2003 ◽  
Vol 144 (11) ◽  
pp. 4755-4762 ◽  
Author(s):  
Pēteris Alberts ◽  
Cecilia Nilsson ◽  
Göran Selén ◽  
Lars O. M. Engblom ◽  
Naimie H. M. Edling ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Selective Inhibition ◽  
Hydroxysteroid Dehydrogenase ◽  
Hepatic Insulin Sensitivity

scholarly journals Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 in Human Fetal Lung and Regulation of Its Expression by Interleukin-1β and Cortisol

2009 ◽  
Vol 94 (1) ◽  
pp. 306-313 ◽  
Author(s):  
Zhen Yang ◽  
Ping Zhu ◽  
Chunming Guo ◽  
Xiaoou Zhu ◽  
Kang Sun
Keyword(s):  
Mrna Expression ◽  
Fetal Lung ◽  
Hydroxysteroid Dehydrogenase ◽  
Cyclooxygenase 2 ◽  
Dominant Negative ◽  
Lung Fibroblasts ◽  
Dependent Manner ◽  
Proinflammatory Mediators ◽  
Human Fetal Lung

Abstract Context: Glucocorticoids are crucial in fetal lung function. The amount of cortisol available to its receptors is increased by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Glucocorticoids and IL-1β are known to induce 11β-HSD1 expression in a number of tissues, but controversial results were obtained with regard to 11β-HSD1 expression in human fetal lung. Objective: We examined the expression of 11β-HSD1 and its regulation by cortisol and IL-1β in human fetal lung. Results: Immunohistochemistry revealed 11β-HSD1 expression in the epithelium and mesenchymal layer of the small bronchus and bronchiole of human fetal lung at 8 months but not at 4 months gestation, which was confirmed by PCR revealing 11β-HSD1 mRNA expression in the fetal lung tissue. By using a cell line derived from human fetal lung fibroblasts, we demonstrated that cortisol (10−5 to 10−3 mmol/liter) or IL-1β (0.1 to 10 ng/ml) induced 11β-HSD1 mRNA expression in a concentration-dependent manner. The induction of 11β-HSD1 by IL-1β was further increased by cortisol, whereas the induction of cyclooxygenase 2 by IL-1β was inhibited by cortisol. Nuclear factor κB activation inhibitor could only block the induction of cyclooxygenase 2 but not 11β-HSD1 by IL-1β, suggesting that different mechanisms were utilized by IL-1β in the regulation of 11β-HSD1 versus proinflammatory mediators. Global inhibition of CCAAT-enhancer-binding proteins (C/EBPs) with transfection of C/EBP-specific dominant-negative expression plasmid could attenuate the induction of 11β-HSD1 by IL-1β, suggesting that C/EBPs may mediate the induction of 11β-HSD1 by IL-1β. Conclusions: 11β-HSD1 is expressed in human fetal lung; cortisol and IL-1β could synergistically induce its expression.

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