Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-pituitary tumors that produce adrenocorticotropic hormone (ACTH) exhibit resistance to the normal feedback effects of glucocorticoids on proopiomelanocortin (POMC) gene expression. This glucocorticoid resistance is typically complete, although some tumors show only relative glucocorticoid resistance in the clinical setting. The molecular mechanisms responsible for these clinical pathophysiologic observations are unknown, but might include glucocorticoid receptor defects or aberrant expression of enzymes or transporters that exclude glucocorticoids from access to their intracellular receptors. We examined whether ACTH-producing non-pituitary tumor cells might express 11beta-hydroxysteroid dehydrogenase (11beta-HSD), the principal 'gatekeeper' enzyme known to metabolize glucocorticoids. 11Beta-HSD mRNA and enzyme activity were assessed in DMS-79 cells, a line derived from an ACTH-producing small cell lung cancer. RT-PCR studies showed expression of mRNA encoding 11beta-HSD2 but not 11beta-HSD1 in DMS-79 cells. Control human fibroblasts expressed predominantly 11beta-HSD1 but also had detectable 11beta-HSD2 mRNA, while HepG2 hepatoma cells also expressed only 11beta-HSD2 mRNA. Whole cell assays in DMS-79 cells revealed 11beta-HSD activity with a Km for cortisol of 26.1 +/- 9.0 nM and Vmax of 57.0 +/- 5.9 pmol/h/mg protein. HepG2 cells expressed a similar high affinity enzyme activity, while control fibroblasts expressed 11beta-HSD activity with a Km for cortisol of 652 nM. Conversion of cortisol to cortisone in DMS-79 cells was inhibited to 7% of baseline by addition of 10 microM glycyrrhetinic acid. Dexamethasone (20 nM) was converted to a single product in DMS-79 cells at a rate of 17.2 pmol/h/mg protein; this activity was also inhibited by glycyrrhetinic acid. We conclude that DMS-79 cells express 11beta-HSD2. While DMS-79 cells harbor additional defects in glucocorticoid signaling, these data suggest that expression of 11beta-HSD2 might contribute to the development of the glucocorticoid-resistant phenotype of some ACTH-producing tumors.
J Steroid Biochem Mol Biol 1998 Nov
PMID:Expression of 11beta-hydroxysteroid dehydrogenase type 2 in an ACTH-producing small cell lung cancer. 988 91

To assess the effect of red wine on atherosclerosis, New Zealand rabbits were given 1% cholesterol diet for 12 weeks and compared to animals that received the diet plus either red wine or nonalcoholic wine products (NAWP). Diet induced marked increases in total and LDL cholesterol; yet no significant changes in HDL and triglyceride concentrations occurred. In the control group, plaque area was 69 +/- 9% of the aortic surface, while in the wine and NAWP groups it was only 38 +/- 9 and 47 +/- 12%, respectively (P < 0.0001). The average intima/media thickness ratio was 0.60 +/- 0.2 in control animals, 0.14 +/- 0.09 in the wine group, and 0.39 +/- 0.19 in the NAWP group (P < 0.0001). No significant differences were noted in LDL oxidizability among treatments. Thus, both red wine and NAWP can prevent plaque formation in hypercholesterolemic rabbits despite significant increases in LDL. We speculate that anti-platelet effect, blockade of expression of endothelial cell adhesion molecules, and/or NO stimulation by red wine flavonoids are possible explanations.
Exp Mol Pathol 1999 Feb
PMID:The effect of red wine on experimental atherosclerosis: lipid-independent protection. 1023 61

Plasma lipid profile and abdominal obesity have been associated with breast cancer risk, however published results have been inconsistent. To clarify these associations we studied lipid and lipoprotein alterations, obesity degree and body fat distribution, in 30 newly diagnosed breast cancer patients without treatment and 30 controls matched by age and menopausal status. Both pre and postmenopausal breast cancer patients presented higher body mass index, waist/hip ratio and insulin levels than their matched controls. An increase in triglycerides and a decrease in HDL-cholesterol, especially in the HDL2 subfraction, were observed in patients with breast cancer. Besides, HDL particle from these patients showed increased apo A1/HDL-cholesterol ratio. These alterations were correlated with waist/hip ratio. The association between lipoprotein alterations and abdominal obesity independent of menopausal status, in untreated newly diagnosed breast cancer patients is reported for the first time in this study.
Biochem Mol Biol Int 1999 Apr
PMID:Lipoprotein alterations, abdominal fat distribution and breast cancer. 1031 21

Long term feeding effects (20 weeks) of heated and fried oils at 5 and 20% level in the diet on growth, plasma and tissue lipids were studied in rats. Three vegetable oils of widespread usage viz., peanut oil, sesame oil and coconut oil with varying saturation and unsaturation were chosen for the study. No significant difference in growth rate, feed efficiency ratio, and liver weights were observed. Higher plasma cholesterol levels were observed in heated oil fed group of rats compared to corresponding fried oil groups. Low levels of HDL-c and increased LDL-c and VLDL-c were noted in heated/fried oil groups. Significantly low levels (p < 0.001) of triglyceride were observed in heated/fried sesame oil group of rats. No significant change in phospholipid was observed in any of the groups. Significantly low levels of liver cholesterol and high triglyceride levels (at 20%) were observed in coconut oil group. The fatty acid composition of plasma and liver reflected the type of diet consumed. Although linoleic acid levels were quite low in some of the heated/fried oil groups the arachidonic acid levels were quite high indicating repair mechanism. The results of the study however do not present any deleterious effect on growth, plasma and tissue lipid profile of rats as the conditions employed for heating/frying were not too drastic and the oils were not heat abused.
Mol Cell Biochem 1999 May
PMID:Long term feeding effects of heated and fried oils on lipids and lipoproteins in rats. 1039 78

Lipoprotein lipase (LPL) is known to be attached to the luminal surface of vascular endothelial cells in a complex with membrane-bound heparan sulfate, and released into blood stream by heparin. LPL that catalyzes hydrolysis of triglyceride (TGL) on chylomicron and VLDL into two fatty acids and monoacylglycerol, is also implicated to participate in an enhancement of cholesterol uptake by arterial endothelial cells in vitro. But little is known about the LPL-mediated cholesterol uptake in physiological state. In this study, changes in blood lipid composition and levels of lipoproteins were determined after the injection of heparin in human. The level of LPL in plasma was increased from 0 to 11 mU/ml within 30-40 min post-heparin administration and decreased to the basal level within 2 h. The level of TGL in plasma decreased from 70 mg/dl to 20 mg/dl within 1 h and gradually increased to 80 mg/dl within 4 h. However the level of total cholesterol in plasma remained at 140 mg/dl during an experimental period of 4 h. Analysis of Lipoproteins in plasma by NaBr density gradient ultracentrifugation showed that the level of VLDL decreased from 50 mg/dl to 10 mg/dl within 1-2 h and returned to normal plasm level at 4 h. However there were no significant changes in the level of LDL and HDL. These results suggest that, at least, in normo-lipidemic subjects, increased free plasm LPL acts primarily on VLDL and failed to show any significant uptake of cholesterol-rich lipoproteins in human.
Exp Mol Med 1999 Jun 30
PMID:Change of plasma lipoproteins by heparin-released lipoprotein lipase. 1041 Mar 3

The 11beta-hydroxysteroid dehydrogenase enzymes (11beta-HSD) interconvert cortisol and cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. Two distantly related congeners have been isolated and conserved domains identified by multiple alignment and hydrophobic cluster analysis. 11Beta-HSD1 in the liver acts mainly as an oxoreductase maintaining circulating glucocorticoid levels. Gene deletion studies suggest it plays an important role in providing elevated local concentrations of hormone. In contrast, 11beta-HSD2 inactivates glucocorticoids and is pivotal in the distal tubule where it protects the mineralocorticoid receptor from occupation, thus endowing specificity on a non-selective receptor. Mutations in 11beta-HSD2 result in sodium retention and severe hypertension, account for the syndrome of apparent mineralocorticoid excess and may be responsible for other forms of hypertension. 11Beta-HSD2 is also present in the placenta where it protects the fetus from high circulating levels of maternal glucocorticoids. Attenuated placental 11beta-HSD2 activity has recently been shown to be associated with intrauterine growth retardation. 11Beta-HSD2 may also play important roles in pulmonary physiology and breast cancer. This review focuses on recent developments.
Mol Cell Endocrinol 1999 May 25
PMID:The 11beta-hydroxysteroid dehydrogenases: functions and physiological effects. 1041 26

The type 2 isozyme of 11beta-hydroxysteroid dehydrogenase inactivates cortisol to cortisone and enables aldosterone to bind to the MR. Congenital deficiency of the enzyme results in cortisol-mediated mineralocorticoid excess and arises because of inactivating mutations in the HSD11B2 gene. Inhibition of the enzyme following licorice or carbenoxolone ingestion results in a similar, though milder phenotype and the enzyme is overwhelmed in ectopic ACTH syndrome. Loss of 11beta-HSD2 expression may be important in sodium balance and blood pressure control in some patients with renal disease. Finally, while some studies demonstrate impaired 11beta-HSD activity in broader populations of patients with hypertension, further studies are required to clarify the role of 11beta-HSD2 in 'essential' hypertension.
J Steroid Biochem Mol Biol
PMID:Cortisol as a mineralocorticoid in human disease. 1041 18

Local tissue concentrations of glucocorticoids are modulated by the enzyme 11beta-hydroxysteroid dehydrogenase which interconverts cortisol and the inactive glucocorticoid cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. The type I isoform (11beta-HSD1) is a bidirectional enzyme but acts predominantly as a oxidoreductase to form the active glucocorticoids cortisol or corticosterone, while the type II enzyme (11beta-HSD2) acts unidirectionally producing inactive 11-keto metabolites. There are no known clinical conditions associated with 11beta-HSD1 deficiency, but gene deletion experiments in the mouse indicate that this enzyme is important both for the maintenance of normal serum glucocorticoid levels, and in the activation of key hepatic gluconeogenic enzymes. Other important sites of action include omental fat, the ovary, brain and vasculature. Congenital defects in the 11beta-HSD2 enzyme have been shown to account for the syndrome of apparent mineralocorticoid excess (AME), a low renin severe form of hypertension resulting from the overstimulation of the non-selective mineralocorticoid receptor by cortisol in the distal tubule of the kidney. Inactivation of the 11beta-HSD2 gene in mice results in a phenotype with similar features to AME. In addition, these mice show high neonatal mortality associated with marked colonic distention, and remarkable hypertrophy and hyperplasia of the distal tubule epithelia. 11Beta-HSD2 also plays an important role in decreasing the exposure of the fetus to the high levels of maternal glucocorticoids. Recent work suggests a role for 11beta-HSD2 in non-mineralocorticoid target tissues where it would modulate glucocorticoid access to the glucocorticoid receptor, in invasive breast cancer and as a mechanism providing ligand for the putative 11-dehydrocorticosterone receptor. While previous homologies between members of the SCAD superfamily have been of the order of 20-30% phylogenetic analysis of a new branch of retinol dehydrogenases indicates identities of > 60% and overlapping substrate specificities. The availability of crystal structures of family members has allowed the mapping of conserved 11beta-HSD domains A-D to a cleft in the protein structure (cofactor binding domain), two parallel beta-sheets, and an alpha-helix (active site), respectively.
J Steroid Biochem Mol Biol
PMID:The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes. 1041 17

11beta-hydroxysteroid dehydrogenase (11betaHSD) reversibly converts hydrocortisone, the predominant active endogenous glucocorticoid in humans, to its inactive metabolite cortisone by oxidizing the 11-hydroxy group to an 11-keto group. Because this enzyme is highly expressed in human bronchial epithelial cells, we hypothesized that it regulates epithelial responses to glucocorticoids by reducing levels of hydrocortisone available to bind to the glucocorticoid receptor. Primary human bronchial epithelial cells (PBECs) were isolated from seven autopsy specimens and cultured in F12/Dulbecco's modified Eagle's medium with 5% fetal bovine serum until approximately 80% confluent. Cells were preincubated with 10(-9) M to 10(-5) M hydrocortisone for 24 h in the presence or absence of 10(-6) M of the 11betaHSD inhibitor glycyrrhetinic acid, after which the cells were stimulated with 5 ng/ml interleukin-1beta for 24 h. Granulocyte macrophage colony-stimulating factor (GM-CSF) levels were quantitated in the resulting supernatants by enzyme-linked immunosorbent assay. Hydrocortisone inhibited GM-CSF release in stimulated PBEC with a concentration that produces 50% inhibition of maximum effect (IC(1/2)max) of 5.0 x 10(-8) M. In the presence of glycyrrhetinic acid, the potency of hydrocortisone was increased approximately 33-fold (IC(1/2)max with glycyrrhetinic acid, 1.5 x 10(-9) M). Hydrocortisone activity was maximally enhanced at concentrations between 10(-9) M and 10(-8) M, levels that are comparable to plasma levels of hydrocortisone not bound to plasma proteins. Glycyrrhetinic acid had no effect on the suppression of GM-CSF release by hydrocortisone in the transformed cell line BEAS-2B, which does not express the 11betaHSD enzyme. Glycyrrhetinic acid also had no effect on the inhibition of GM-CSF release in PBECs by the synthetic glucocorticoids budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide, steroids not metabolized by 11betaHSD. Together, these findings suggest that metabolism of hydrocortisone by 11betaHSD may regulate glucocorticoid activity in human airway epithelial cells.
Am J Respir Cell Mol Biol 1999 Sep
PMID:Regulation of the action of hydrocortisone in airway epithelial cells by 11beta-hydroxysteroid dehydrogenase. 1046 Jul 58

We have investigated hepatic expression and glucocorticoid regulation of the corticosteroid-binding globulin (CBG) gene in mice lacking a functional glucocorticoid receptor (GR). GR-/- mice show impaired negative feedback in the hypothalamic-pituitary-adrenal axis, resulting in elevated circulating levels of ACTH and corticosterone. This is seen in the neonatal period and continues into adulthood where ACTH and corticosterone levels are increased up to 4-5 fold. Despite high elevation of corticosterone we find no change in mean arterial blood pressure in GR-/- mice and no change in the renal activity of the glucocorticoid-metabolising enzymes 11beta-hydroxysteroid dehydrogenase type-1 (HSD1) and type-2 (HSD2). We do find markedly increased hepatic expression of CBG with a 50% increase in plasma CBG levels. Increased expression of CBG was detected in adult GR-/- mice and also at birth with a greater than 10-fold increase in CBG hepatic mRNA in day-18.5 embryonic GR-/- mice. Adult GR-/- mice were also resistant to dexamethasone-induced repression of CBG expression in the liver. These results indicate that in mice, GR is essential for maintaining the basal level of CBG gene expression in the liver, and is also required for dexamethasone-induced repression of the CBG gene in the adult.
Mol Cell Endocrinol 1999 Aug 20
PMID:The glucocorticoid receptor is essential for maintaining basal and dexamethasone-induced repression of the murine corticosteroid-binding globulin gene. 1050 97


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