Cloning, expression, and tissue distribution of the rat nicotinamide adenine dinucleotide-dependent 11 beta-hydroxysteroid dehydrogenase.

Zhou, Mingyi; Gómez-Sánchez, Elise P.; Cox, Diana L.; Cosby, D.; Gómez-Sánchez, Celso E.

doi:10.1210/endo.136.9.7649078

Cited by 82 publications

(24 citation statements)

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“…Leydig cells contain type I 11␤-HSD (8,9), an oxidoreductase that has been shown to be primarily reductive when its activity was assayed in liver parenchymal cells (11,13). The type II 11␤-HSD is oxidative but is not detected in Leydig cells (7,27). The present study confirmed that 11␤-HSD activity in liver parenchymal cells is primarily reductive under the same conditions that showed the predominance of oxidative activity in Leydig cells.…”

Section: Discussionsupporting

confidence: 84%

Hormonal Regulation of Oxidative and Reductive Activities of 11 -Hydroxysteroid Dehydrogenase in Rat Leydig Cells

Gao¹

1997

Endocrinology

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We have proposed that the 11␤-hydroxysteroid dehydrogenase (11␤-HSD) of Leydig cells protects against glucocorticoid-induced inhibition of testosterone (T) production. However, Leydig cells express type I 11␤-HSD, which has been shown to be reductive in liver parenchymal cells. Because reduction would have the opposite effect of activating glucocorticoid, the present study was designed to determine: 1) whether Leydig cell 11␤-HSD is primarily oxidative or reductive; and 2) whether oxidative and reductive activities are separately modified by known regulators of Leydig cell steroidogenic function. Leydig cells and liver parenchymal cells were purified from mature male Sprague-Dawley rats (250 g BW), and 11␤-HSD oxidative and reductive activities were measured using radiolabeled substrates and TLC of triplicate media samples from 1-h incubations immediately after cell isolation. Enzyme activities also were examined in purified Leydig cells at the end of 3 days of culture in vitro in the presence of LH (10 ng/ml), dexamethasone (DEX, 100 nM), T (50 nM), or epidermal growth factor (EGF, 50 ng/ml). In confirmation of previous reports, the reductive activity of 11␤-HSD was predominant over oxidation in liver parenchymal cells. In contrast, 11␤-HSD oxidative activity prevailed over reduction in Leydig cells by a ratio of 2:1. The activities of 11␤-HSD also were analyzed in Leydig cells that were purified 7 days after endogenous glucocorticoid levels were suppressed by adrenalectomy (ADX). Oxidative activity declined in Leydig cells after ADX (22.53 Ϯ 1.12 pmol/h⅐10 6 cells, mean Ϯ SEM vs. 31.47 Ϯ 1.48 pmol/h⅐10 6 cells in sham-operated controls, P Ͻ 0.05), whereas there was no change in reductive activity. This indicated that physiologically active corticosterone is involved in maintaining the predominance of 11␤-HSD oxidation. When enzyme activities were analyzed in Leydig cells after 3 days of hormonal treatment in vitro, oxidation and reduction were observed to change in opposing directions. Culture of Leydig cells from sham-operated control rats with either LH, T, or EGF resulted in declines in oxidative activity from 33.35 Ϯ 0.77 to 28.24 Ϯ 1.93, 27.30 Ϯ 0.96, and 24.13 Ϯ 1.02 pmol/ h⅐10 6 cells (x Ϯ SE), respectively. However, EGF stimulated 11␤-HSD reductive activity in cultured Leydig cells from both control (from 18.97 Ϯ 1.10 to 27.16 Ϯ 0.71 pmol/h⅐10 6 cells and ADX rats (from 16.51 Ϯ 0.75 to 23.56 Ϯ 0.84 pmol/h⅐10 6 cells). Among the hormonal treatments, only DEX increased oxidative activity and simultaneously decreased reductive activity in Leydig cells from ADX rats. This increase accentuated the predominance of oxidative activity in Leydig cells, with a ratio of oxidative to reductive activity of 4:1 after DEX treatment, compared with 2:1 in controls that were untreated. We conclude that 11␤-HSD activity in Leydig cells is primarily oxidative. Moreover, oxidation and reduction are regulated separately by hormones. (Endocrinology 138: 156 -161, 1997)

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Section: Discussionsupporting

confidence: 84%

Hormonal Regulation of Oxidative and Reductive Activities of 11 -Hydroxysteroid Dehydrogenase in Rat Leydig Cells

Gao¹

1997

Endocrinology

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“…Expression of two such enzymes, Srd5a1 and Hsd11b2, which catalyze the conversion of glucocorticoids to less active metabolites [44][45][46], were increased in immature adrenals after chronic ACTH exposure. In rats of both sexes, gonadectomy reduces the output of corticosterone from the adrenal gland [47,48] and increases the expression and activity of Srd5a1 [49,50].…”

Section: Discussionmentioning

confidence: 99%

Gene array analysis of the effects of chronic adrenocorticotropic hormone in vivo on immature rat adrenal glands

Lee¹,

Widmaier²

2005

The Journal of Steroid Biochemistry and Molecular Biology

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“…Expression of mRNA for 11b-HSD1 has been demonstrated in several tissues, principally those with high levels of GR but low levels of MR, suggesting that this isozyme serves to modulate the access of glucocorticoids to the GR [Krozowski and Stewart, 1999]. In contrast, 11b-HSD2 is a unidirectional, high af®nity, NAD-dependent dehydrogenase [Albiston et al, 1994;Zhou et al, 1995]. 11b-HSD2 is found predominantly in mineralocorticoid target tissues where it serves to protect the MR from non-selective occupation by glucocorticoids [Edwards et al, 1988;Funder et al, 1988].…”

Section: Discussionmentioning

confidence: 99%

Expression of 11?-hydroxysteroid dehydrogenase in rat osteoblastic cells: Pre-receptor regulation of glucocorticoid responses in bone

et al. 2001

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11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) acts as a pre-receptor signaling mechanism for corticosteroids by regulating the access of active glucocorticoids to both glucocorticoid (GR) and mineralocorticoid receptors (MR). To examine the relationship between endogenous glucocorticoid metabolism and osteoblast function, we have characterized the expression of 11 beta-HSD isozymes in rat osteosarcoma cells. Analysis of mRNA from ROS 25/1, UMR 106 and ROS 17/2.8 cells revealed transcripts for both 11 beta-HSD type 1 (11 beta-HSD1) and type 2 (11 beta-HSD2) in all three cell lines. However, enzyme activity studies showed only high affinity dehydrogenase activity (inactivation of corticosterone (B) to 11-dehydrocorticosterone (A)), characteristic of 11 beta-HSD2; conversion of B to A was higher in ROS 25/1> UMR 106 cells>ROS 17/2.8. Although all three cell lines had similar numbers of GR (50,000/cell), glucocorticoid modulation of alkaline phosphatase activity and cell proliferation was only detectable in ROS 17/2.8 cells. Further studies showed that 11 beta-HSD2 activity in each of the cells was potently stimulated by both A and B, but not by synthetic dexamethasone. This effect was blocked by the 11 beta-HSD inhibitor, 18 beta-glycyrrhetinic acid (but not by GR or MR antagonists) suggesting direct, allosteric regulation of 11 beta-HSD2 activity. These data indicate that in osteosarcoma cells 11 beta-HSD2 plays a key role in controlling GR-mediated responses; cells with relatively high levels of 11 beta-HSD2 activity were insensitive to glucocorticoids, whilst cells with low levels showed functional responses to both dexamethasone and B. In addition to the established effects of 11 beta-HSD2 in protecting MR in the kidney and colon, our data suggest that 11 beta-HSD2 in bone represents an important pre-receptor mechanism in determining ligand availability to GR.

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Cloning, expression, and tissue distribution of the rat nicotinamide adenine dinucleotide-dependent 11 beta-hydroxysteroid dehydrogenase.

Cited by 82 publications

References 0 publications

Hormonal Regulation of Oxidative and Reductive Activities of 11 -Hydroxysteroid Dehydrogenase in Rat Leydig Cells

Hormonal Regulation of Oxidative and Reductive Activities of 11 -Hydroxysteroid Dehydrogenase in Rat Leydig Cells

Gene array analysis of the effects of chronic adrenocorticotropic hormone in vivo on immature rat adrenal glands

Expression of 11?-hydroxysteroid dehydrogenase in rat osteoblastic cells: Pre-receptor regulation of glucocorticoid responses in bone

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