Effects of 22S-hydroxy-cholesterol and other hydroxylated sterols on the ACTH-stimulated steroid production in rat adrenal cells

1981 ◽  
Vol 97 (2) ◽  
pp. 243-250 ◽  
Author(s):  
J. G. M. Huijmans ◽  
H. J. Degenhart ◽  
D. J. Kortleve ◽  
H. K. A. Visser
Keyword(s):  
Cholesterol Metabolism ◽  
Cellular Membrane ◽  
Inhibitory Effect ◽  
Cholesterol Concentration ◽  
Side Chain ◽  
Steroid Production ◽  
Adrenal Cells ◽  
Chain Cleavage ◽  
Coa Reductase ◽  
Hydrolysis Of

Abstract. Several effects of hydroxylated sterols on cell cultures are known. Most of these can be explained by an inhibition of the cholesterol synthesis at the level of the 3-hydroxy-3-methylglutaryl CoA reductase. When studying cholesterol metabolism in rat adrenal cells, an inhibitory action of some sterols on the ACTH-stimulated corticosterone production was observed. The effects of one sterol, 22S-OH-cholesterol, were investigated further. The sterol had no effect on the ACTH-stimulated cyclic AMP production, suggesting an intact receptor-adenylate cyclase complex and cellular membrane. In the presence of ACTH and 22S-OH-cholesterol particularly the free cholesterol concentration was elevated; 22S-OH-cholesterol therefore probably exerts its inhibitory effect at a step located after hydrolysis of the cholesterol esters. 22S-OH-cholesterol had no effect on the conversion of exogenous pregnenolone into corticosterone. These results make it probable, that the inhibitory effect of 22S-OH-cholesterol on the ACTH-stimulated corticosterone production is situated at the level of the cholesterol side-chain cleavage.

Conversion of 22S-hydroxy-cholesterol and its effect on the metabolism of other sterols in rat adrenal cells and bovine adrenal mitochondria

1982 ◽  
Vol 100 (4) ◽  
pp. 599-605 ◽  
Author(s):  
J. G. M. Huijmans ◽  
H. J. Degenhart ◽  
D. J. Kortleve
Keyword(s):  
Causal Relationship ◽  
Enzyme System ◽  
Inhibitory Effect ◽  
Side Chain ◽  
Steroid Production ◽  
Adrenal Cell ◽  
Adrenal Cells ◽  
Side Chain Cleavage ◽  
Chain Cleavage ◽  
Isolated Rat

Abstract. This study provides evidence that 22S-OH-cholesterol inhibits the conversion of 25-OH-cholesterol but has no effect on the conversion of 22R-OH-cholesterol. The latter sterol is an intermediate in the cholesterol side-chain cleavage, whereas for the conversion of 25-OH-cholesterol into pregnenolone the complete side-chain cleaving enzyme system is necessary. This complements a previous study in which it was shown, that 22S-OH-cholesterol has an inhibitory effect on the ACTH-induced conversion of cholesterol into corticosterone in isolated rat adrenal cells. The available evidence thus suggests an inhibition by 22S-OH-cholesterol of the first step in the cholesterol side-chain cleavage. The results, obtained from the experiments with rat adrenal cells and with bovine adrenal mitochondria, allow the hypothesis, that a causal relationship exists between conversion of 22S-OH-cholesterol and production of corticosterone, respectively pregnenolone. We conclude, that 22S-OH-cholesterol is a substrate for steroid production in the adrenal cell. This sterol inhibits the ACTH-stimulated corticosterone production. The site of this inhibition is located at one of the first steps in the cholesterol side-chain cleavage, probably the binding of cholesterol to the cytochrome P450-complex.

Effects of some hydroxylated sterols on the steroid production in isolated rat adrenal glomerulosa and fasciculata/reticularis cells in the presence of potassium, angiotensin II or ACTH

1984 ◽  
Vol 105 (3) ◽  
pp. 411-416
Author(s):  
J. G. M. Huijmans ◽  
H. E. Falke ◽  
H.J. Degenhart
Keyword(s):  
Cholesterol Concentration ◽  
Side Chain ◽  
Steroid Production ◽  
Side Chain Cleavage ◽  
Rate Limiting Step ◽  
Chain Cleavage ◽  
Exogenous Substrate ◽  
Aldosterone Production ◽  
Isolated Rat

Abstract. 22S-OH-cholesterol and 25-OH-cholesterol are good aldosterone precursors in isolated rat adrenal glomerulosa cells. In the two concentrations tested (25 and 50 μm) 25-OH-cholesterol stimulated the aldosterone production in a (not-linear) dose-dependent way. An increase in the 22S-OH-cholesterol concentration from 25 μm to 50 μm led to a decrease in the aldosterone production. The exogenous substrate deoxycorticosterone, entering the steroidogenic pathway after the cholesterol side-chain cleavage, is a much better substrate than the sterols mentioned. These results suggest that the cholesterol side-chain cleavage is the rate-limiting step in the aldosterone production from both sterols. We found no effect of the sterols on the potassiuminduced aldosterone synthesis. This might be explained by the existence of separate pools of steroid intermediates within the adrenal cell. In vitro a difference in steroid production rates exists between glomerulosa and fasciculata/reticularis cells. This may arise from differences in availability of endogenous steroid precursors like cholesterol. However similar differences can be observed if exogenous substrates like 25-OH-cholesterol or 22S-OH-cholesterol are used. These results therefore suggest that enzymatic activities in the steroidogenic pathway are more important than the cholesterol concentration in regulating steroid production in isolated rat adrenal glomerulosa and fasciculata/reticularis cells.

Insulin-like growth factor I enhancement of steroidogenesis by bovine granulosa cells and thecal cells: dependence on de novo cholesterol synthesis

1996 ◽  
Vol 151 (3) ◽  
pp. 365-373 ◽  
Author(s):  
L J Spicer ◽  
T D Hamilton ◽  
B E Keefer
Keyword(s):  
Granulosa Cells ◽  
Cholesterol Synthesis ◽  
De Novo ◽  
Side Chain ◽  
Side Chain Cleavage ◽  
Chain Cleavage ◽  
Thecal Cells ◽  
Igf I ◽  
Cleavage Enzyme ◽  
Coa Reductase

Abstract Studies were conducted to determine the importance of de novo cholesterol synthesis and cholesterol side-chain cleavage enzyme in the action of IGF-I in bovine granulosa and thecal cells. Granulosa and thecal cells from bovine follicles were cultured for 2 days in 10% fetal calf serum and then treated with luteinizing hormone (100 ng/ml) and IGF-I (0 or 100 ng/ml) for an additional 2 days in serum-free medium. During the last 24 h of treatment, cells were concomitantly treated with simvastatin (0, 0·5 or 5 μg/ml) or 25-hydroxycholesterol (0 or 10 μg/ml). Simvastatin, a potent inhibitor of the key enzyme controlling de novo cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, completely inhibited (P<0·05) progesterone production by granulosa cells and progesterone and androstenedione production by thecal cells. Simvastatin also inhibited (P<0·05) granulosa cell and thecal cell proliferation. Concomitant treatment with mevalonate, an immediate product of HMG-CoA reductase, attenuated the inhibitory effect of simvastatin on progesterone and androstenedione production by thecal cells and blocked the inhibitory effect of simvastatin on cell proliferation. The addition of 25-hydroxycholesterol, a substrate for cholesterol side-chain cleavage enzyme, had no effect (P>0·10) on IGF-I-stimulated progesterone or androstenedione production by thecal cells and actually inhibited (P<0·05) IGF-I-stimulated progesterone production by granulosa cells. These results provide indirect evidence indicating that stimulation of HMG-CoA reductase is an important locus of IGF-I action in bovine granulosa and thecal cells, whereas IGF-I has little or no effect on side-chain cleavage enzyme activity in these same cell types under the culture conditions employed. Journal of Endocrinology (1996) 151, 365–373

scholarly journals Anti-HMG-CoA Reductase, Antioxidant, and Anti-Inflammatory Activities ofAmaranthus viridisLeaf Extract as a Potential Treatment for Hypercholesterolemia

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Shamala Salvamani ◽  
Baskaran Gunasekaran ◽  
Mohd Yunus Shukor ◽  
Noor Azmi Shaharuddin ◽  
Mohd Khalizan Sabullah ◽  
...  
Keyword(s):  
Leaf Extract ◽  
Cholesterol Metabolism ◽  
Inhibitory Effect ◽  
Hmg Coa Reductase ◽  
Synthetic Drugs ◽  
Reductase Inhibitors ◽  
Plot Analysis ◽  
Hmg Coa Reductase Inhibitors ◽  
Anti Inflammatory ◽  
Coa Reductase

Inflammation and oxidative stress are believed to contribute to the pathology of several chronic diseases including hypercholesterolemia (elevated levels of cholesterol in blood) and atherosclerosis. HMG-CoA reductase inhibitors of plant origin are needed as synthetic drugs, such as statins, which are known to cause adverse effects on the liver and muscles.Amaranthus viridis(A. viridis) has been used from ancient times for its supposedly medically beneficial properties. In the current study, different parts ofA. viridis(leaf, stem, and seed) were evaluated for potential anti-HMG-CoA reductase, antioxidant, and anti-inflammatory activities. The putative HMG-CoA reductase inhibitory activity ofA. viridisextracts at different concentrations was determined spectrophotometrically by NADPH oxidation, using HMG-CoA as substrate.A. viridisleaf extract revealed the highest HMG-CoA reductase inhibitory effect at about 71%, with noncompetitive inhibition in Lineweaver-Burk plot analysis. The leaf extract showed good inhibition of hydroperoxides, 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), and ferric ion radicals in various concentrations.A. viridisleaf extract was proven to be an effective inhibitor of hyaluronidase, lipoxygenase, and xanthine oxidase enzymes. The experimental data suggest thatA. viridisleaf extract is a source of potent antioxidant and anti-inflammatory agent and may modulate cholesterol metabolism by inhibition of HMG-CoA reductase.

Selective aromatase inhibition by pyridoglutethimide, an analogue of aminoglutethimide

1990 ◽  
Vol 122 (5) ◽  
pp. 592-598 ◽  
Author(s):  
Jo Kitawaki ◽  
Takara Yamamoto ◽  
Mamoru Urabe ◽  
Takaya Tamura ◽  
Shigeo Inoue ◽  
...  
Keyword(s):  
Competitive Inhibition ◽  
Inhibitory Effect ◽  
Side Chain ◽  
Aromatase Activity ◽  
Inhibitory Effects ◽  
Metabolizing Enzymes ◽  
Chain Cleavage ◽  
Steroid Hydroxylases ◽  
Cytochrome P 450

Abstract. The inhibitory effects of pyridoglutethimide (3-ethyl-3-(4-pyridyl)piperidine-2,6-dione), an analogue of aminoglutethimide, on aromatase and other cytochrome P-450-dependent steroid-metabolizing enzymes were studied in vitro. Pyridoglutethimide and aminoglutethimide showed competitive inhibition of human placental aromatase activity with apparent Ki values of 1.7 and 0.7 μmol/l, respectively. Both pyridoglutethimide and aminoglutethimide inhibited the aromatase activity of uterine leiomyoma and cultured choriocarcinoma Enami cells as well as immunopurified human placental aromatase cytochrome P-450 by more than 90%, with IC50 values of 10–19 and 5–7 μmol/l, respectively. These results might suggest that the inhibitors interacted directly with the aromatase cytochrome P-450 of these tissues. Aminoglutethimide inhibited bovine adrenal cholesterol side-chain cleavage activity with an IC50 value of 40 μmol/l and inhibited 21-hydroxylase activity slightly, but did ot inhibit 17α-, 1 1β- and 18-hydroxylase at concentrations up to 100 μmol/l. On the other hand, pyridoglutethimide had no inhibitory effect on any of these enzymes at concentrations up to 50 μmol/l, although it inhibited 11β- and 18-hydroxylase slightly at 100 μmol/l. These results indicated that pyridoglutethimide was an aromatase inhibitor of a comparable potency to aminoglutethimide, but that it did not inhibit other steroid hydroxylases.

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