Licorice Inhibits Corticosteroid 1lβ-Dehydrogenase of Rat Kidney and Liver:<i>In Vivo</i>and<i>in Vitro</i>Studies*

Monder, Carl; Stewart, Paul M.; Lakshmi, Vijaya M.; Valentino, Rossella; Burt, D.; Edwards, C. R. W.

doi:10.1210/endo-125-2-1046

Cited by 309 publications

(130 citation statements)

References 40 publications

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“…synthesised in-house as described previously (Bujalska et al 1997). Whole tissue and primary cultures were incubated with GC substrates as described earlier and a 100-fold excess (4$707!10 K3 mg/ml) of glycyrrhetinic acid (GE; Sigma), an inhibitor of 11b-HSDs (Monder et al 1989). After 24 h incubation, steroids were extracted from the medium with 10 volumes of dichloromethane separated by thin-layer chromatography with chloroform:ethanol (92:8) as a mobile phase and the fractional conversion of cortisol to cortisone or cortisone to cortisol was calculated after scanning analysis using a Bioscan 2000 radioimaging detector (Bioscan, Washington, DC, USA).…”

Section: B-hsd1 Enzyme Assaysmentioning

confidence: 99%

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Onyimba¹,

Vijapurapu²,

Curnow³

et al. 2006

Journal of Endocrinology

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The prereceptor regulation of glucocorticoids (GCs) by 11b-hydroxysteroid dehydrogenase type-1 (11b-HSD1), a bidirectional isozyme that interconverts active (cortisol) and inactive (cortisone) GCs, is an established determinant of GC function in tissues such as liver, adipose and bone. Although the therapeutic use of GCs is abundant in ophthalmic practice, where GC interactions with nuclear receptors modulate gene transcription, the prereceptor regulation of endogenous cortisol is not well described in ocular tissues. Recent descriptive studies have localised 11b-HSD1 to the human corneal epithelium and non-pigmented epithelium (NPE) of the ciliary body, indicating a link to corneal epithelial physiology and aqueous humour production. In this study, we characterise the functional aspects of the autocrine regulation of GCs in the anterior segment of the rabbit eye. Using our in-house generated primary antibody to human 11b-HSD1, immunohistochemical analyses were performed on paraffin-embedded sections of whole New Zealand white albino rabbits, (NZWAR) eyes. As in human studies, 11b-HSD1 was localised to the corneal epithelium and the NPE. No staining was seen in the albino 'pigmented' ciliary epithelium. Specific enzyme assays for oxo-reductase (cortisone/cortisol) and dehydrogenase (cortisol/cortisone) activity indicated predominant 11b-HSD1 oxo-reductase activity from both the intact ciliary body tissue (nZ12, median 2$1 pmol/mg per h and range 1$25-2$8 pmol/mg per h; PZ0$006) and primary cultures of corneal epithelial cells (nZ12, median 3$0 pmol/mg per h and range 1$0-7$4 pmol/mg per h, PZ0$008) compared with dehydrogenase activity (median 1$0 pmol/mg per h and range 0$5-2$0 pmol/mg per h; median 0$5 pmol/mg per h and range 0$25-1$9 pmol/mg per h respectively). These findings were supported by expression of 11b-HSD1 protein as visualised by Western blotting of ciliary body tissue and immunocytochemistry of corneal epithelial cells. Reduction of corneal epithelial cell proliferation was seen after primary cultures were co-incubated with cortisol and cortisone. 11b-HSD1 activity was not demonstrated in naïve conjunctival fibroblasts or corneal stromal keratocytes. Our results indicate that the distribution of 11b-HSD1 in the rabbit resembles that of the human eye and activates cortisone to cortisol in both corneal and uveal tissues. The NZWAR provides a suitable in vivo model for the further evaluation of 11b-HSD1 activity in the eye, especially its role in corneal epithelial and ciliary body physiology.

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Section: B-hsd1 Enzyme Assaysmentioning

confidence: 99%

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Onyimba¹,

Vijapurapu²,

Curnow³

et al. 2006

Journal of Endocrinology

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“…The beneficial effect of 11b-HSD1 inhibition on insulin tolerance has been reported in both healthy men and type 2 diabetic patients using CBX despite impaired cortisol inactivation within MR target tissues via inhibition of 11b-HSD2 (Monder et al 1989, Walker et al 1995, Andrews et al 2003. Similarly, CBX attenuated hepatic insulin tolerance and improved lipid metabolism in rodents (Saegusa et al 1999, Nuotio-Antar et al 2007, although it did not reduce insulin resistance in obese Zucker rats (Livingstone & Walker 2003).…”

Section: Introductionmentioning

confidence: 96%

Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

Liu

Nakagawa²,

Wang³

et al. 2008

Journal of Molecular Endocrinology

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Intracellular glucocorticoid (GC) receptor (GR) function determines tissue sensitivity to GCs and strongly affects the development of type 2 diabetes and obesity. 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) mediates intracellular steroid exposure to mouse liver GR by prereceptor reactivation of GCs and is crucially dependent on hexose-6-phosphate dehydrogenase (H6PDH)-generating NADPH system. Pharmacological inhibition of 11b-HSD1 improves insulin intolerance and obesity. Here, we evaluated the potential beneficial effects of 11b-HSD1 inhibitor carbenoxolone (CBX) in diet-induced obese (DIO) and insulin-resistant mice by examining the possible influence of CBX on the expression of GR, 11b-HSD1, and H6PDH in vivo and in vitro in hepatocytes. Treatment of DIO mice with CBX markedly reduced hepatic GR mRNA levels and reduced weight gain, hyperglycemia, and insulin resistance. The reduction of hepatic GR gene expression was accompanied by CBX-induced inhibition of both 11b-HSD1 and H6PDH activity and mRNA in the liver. Moreover, CBX treatment also suppressed the expression of both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase enzyme (G6Pase) mRNA and improved hepatic [1,[2][3] H] deoxy-D-glucose uptake in DIO mice. In addition, the treatment of primary cultures of hepatocytes with increasing concentrations of CBX led to a dose-dependent downregulation of GR mRNA levels, which correlated with the suppression of both 11b-HSD1 and H6PDH activity and their gene expression. Addition of CBX to primary hepatocytes also resulted in suppression of both PEPCK and G6Pase mRNA levels. These findings suggest that CBX exerts some of its beneficial effects, at least in part, by inhibiting hepatic GR and H6PDH expression.

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“…The activity of the 11␤HSD2 is potently blocked in vivo and in vitro by glycyrrhetinic acid (GA), the active compound of liquorice by two mechanisms, direct competitive inhibition (20) and pretranslational inhibition (21). Thus, the administration of high doses of GA (22) and mutations in 11␤HSD2 are phenotypically identical.…”

mentioning

confidence: 99%

Modulation of Renal Calcium Handling by 11β-Hydroxysteroid Dehydrogenase Type 2

Ferrari

Bianchetti²,

Sansonnens³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Reduced concentration of serum ionized calcium and increased urinary calcium excretion have been reported in primary aldosteronism and glucocorticoid-treated patients. A reduced activity of the 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) results in overstimulation of the mineralocorticoid receptor by cortisol. Whether inhibition of the 11␤HSD2 by glycyrrhetinic acid (GA) may increase renal calcium excretion is unknown. Serum and urinary electrolyte and creatinine, serum ionized calcium, urinary calcium excretion, and the steroid metabolites (THFϩ5␣THF)/THE as a parameter of 11␤HSD2 activity were repeatedly measured in 20 healthy subjects during baseline conditions and during 1 wk of 500 mg/d GA. One week of GA induced a maximal increment of 93% in (THFϩ5␣THF)/THE. Ambulatory BP was significantly higher at day 7 of GA than at baseline (126/77 Ϯ 10/7 versus 115/73 Ϯ 8/6 mmHg; P Ͻ 0.001 for systolic; P Ͻ 0.05 for diastolic). During GA administration, serum ionized calcium decreased from 1.26 Ϯ 0.05 to 1.18 Ϯ 0.04 mmol/L (P Ͻ 0.0001), and absolute urinary calcium excretion was enhanced from 29.2 Ϯ 3.6 to 31.9 Ϯ 3.1 mol/L GFR (P Ͻ 0.01). Fractional calcium excretion increased from 2.4 Ϯ 0.3 to 2.7 Ϯ 0.3% (P Ͻ 0.01) and was negatively correlated to the fractional sodium excretion during GA (R ϭ Ϫ0.35; P Ͻ 0.001). Moreover, serum potassium correlated positively with serum ionized calcium (R ϭ 0.66; P Ͻ 0.0001). Inhibition of 11␤HSD2 activity is sufficient to significantly increase the fractional excretion of calcium and decrease serum ionized calcium, suggesting decreased tubular reabsorption of this divalent cation under conditions of renal glucocorticoid/mineralocorticoid excess. The likely site of steroid-regulated renal calcium handling appears to be the distal tubule.

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Licorice Inhibits Corticosteroid 1lβ-Dehydrogenase of Rat Kidney and Liver:In Vivoandin VitroStudies*

Cited by 309 publications

References 40 publications

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice

Modulation of Renal Calcium Handling by 11β-Hydroxysteroid Dehydrogenase Type 2

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