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Endocrinology, Vol 136, 4754-4761, Copyright © 1995 by Endocrine Society
ARTICLES |
PM Jamieson, KE Chapman, CR Edwards and JR Seckl
University of Edinburgh, Department of Medicine, Western General Hospital, Scotland.
11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the conversion of corticosterone to inert 11-dehydrocorticosterone, thus regulating glucocorticoid access to intracellular receptors. This type 1 isoform (11 beta HSD-1) is a bidirectional NADPH(H)-dependent enzyme in vitro and is highly expressed in liver, where it is regulated by glucocorticoids, thyroid hormones, estrogen, and GH in vivo. In humans in vivo, enzyme inhibition alters glucose homeostasis, an effect thought to be mediated in the liver. However, detailed investigation of the biology of 11 beta HSD-1 in liver, its function, regulation, and indeed even reaction direction, has been hampered by the lack of clonal hepatic cell lines that express 11 beta HSR-1. Studies of nonhepatic cell lines have suggested that 11 beta HSD-1 is directly regulated by hormones, and transfection of nonhepatic cell lines has sown that reaction direction varies between cell types, possibly reflecting intracellular cosubstrate (NADP+/NADPH) ratios or PH. To investigate reaction direction and gene regulation of 11 beta HSD-1 in hepatocytes, we defined conditions for primary culture of adult rat hepatocytes that maintain high 11 beta HSR-1 messenger RNA expression. In intact primary hepatocytes over a wide range of steroid concentrations (2.5-250 nM), 11 beta-reduction was the predominant reaction direction [33.5 +/- 0.5% conversion of 11-dehydrocorticosterone (25 nM) to corticosterone after 30 min], with undetectable 11 beta-dehydrogenation. However, homogenates of hepatocyte cultures showed plentiful 11 beta- dehydrogenase activity. Treatment of hepatocyte cultures with the metabolic inhibitors sodium azide (5 nM) and KCN (1 nM) altered cellular NADP+/NADPH ratios from 0.244 +/- 0.042 in controls to 0.020 +/- 0.001 and 0.152 +/- 0.009, respectively, but had no effect on 11 beta-reductase or 11 beta- dehydrogenase activity. High concentrations of KCN (10 mM) modestly increased 11 beta-reductase activity (32.4 +/- 1.7% to 48.8 +/- 0.5%, whereas 11 beta-dehydrogenation remained at the limit of detection. Manipulation of culture medium pH (6.2-8.0) had no effect on enzyme activity. Dexamethasone (10-7 M) induced hepatocyte 11 beta-reductase activity from 23.4 +/- 0.7% to only weakly affects reaction direction. Glucocorticoid and insulin regulation of hepatic 11 beta HSD-1 is directly mediated, but other hormonal controls are either lost in culture or mediated indirectly. This primary hepatocyte culture system will allow investigation of the control of 11 beta-reductase activity and its implications for glucocorticoid-regulated hepatic functions.
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A. Nordenström, C. Marcus, M. Axelson, A. Wedell, and E. M. Ritzén Failure of Cortisone Acetate Treatment in Congenital Adrenal Hyperplasia because of Defective 11{beta}-Hydroxysteroid Dehydrogenase Reductase Activity J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1210 - 1213. [Abstract] [Full Text] |
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P. M. Stewart, A. Boulton, S. Kumar, P. M. S. Clark, and C. H. L. Shackleton Cortisol Metabolism in Human Obesity: Impaired Cortisone->Cortisol Conversion in Subjects with Central Adiposity J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1022 - 1027. [Abstract] [Full Text] |
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J. Tremblay, D.B. Hardy, L.E. Pereira, and K. Yang Retinoic Acid Stimulates the Expression of 11ß-Hydroxysteroid Dehydrogenase Type 2 in Human Choriocarcinoma JEG-3 Cells Biol Reprod, March 1, 1999; 60(3): 541 - 545. [Abstract] [Full Text] |
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P. J. Burton and B. J. Waddell Dual Function of 11ß-Hydroxysteroid Dehydrogenase in Placenta: Modulating Placental Glucocorticoid Passage and Local Steroid Action Biol Reprod, February 1, 1999; 60(2): 234 - 240. [Abstract] [Full Text] [PDF] |
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J. Condon, C. Gosden, D. Gardener, P. Nickson, M. Hewison, A. J. Howie, and P. M. Stewart Expression of Type 2 11{beta}-Hydroxysteroid Dehydrogenase and Corticosteroid Hormone Receptors in Early Human Fetal Life J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4490 - 4497. [Abstract] [Full Text] |
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M. Panarelli, C. D. Holloway, R. Fraser, J. M. C. Connell, M. C. Ingram, N. H. Anderson, and C. J. Kenyon Glucocorticoid Receptor Polymorphism, Skin Vasoconstriction, and Other Metabolic Intermediate Phenotypes in Normal Human Subjects J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 1846 - 1852. [Abstract] [Full Text] |
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M. L. Ricketts, J. M. Verhaeg, I. Bujalska, A. J. Howie, W. E. Rainey, and P. M. Stewart Immunohistochemical Localization of Type 1 11{beta}-Hydroxysteroid Dehydrogenase in Human Tissues J. Clin. Endocrinol. Metab., April 1, 1998; 83(4): 1325 - 1335. [Abstract] [Full Text] |
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B. J. Waddell, R. Benediktsson, R. W. Brown, and J. R. Seckl Tissue-Specific Messenger Ribonucleic Acid Expression of 11{beta}-Hydroxysteroid Dehydrogenase Types 1 and 2 and the Glucocorticoid Receptor within Rat Placenta Suggests Exquisite Local Control of Glucocorticoid Action Endocrinology, April 1, 1998; 139(4): 1517 - 1523. [Abstract] [Full Text] [PDF] |
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R. Diaz, R. W. Brown, and J. R. Seckl Distinct Ontogeny of Glucocorticoid and Mineralocorticoid Receptor and 11beta -Hydroxysteroid Dehydrogenase Types I and II mRNAs in the Fetal Rat Brain Suggest a Complex Control of Glucocorticoid Actions J. Neurosci., April 1, 1998; 18(7): 2570 - 2580. [Abstract] [Full Text] [PDF] |
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P. J. Burton, Z. S. Krozowski, and B. J. Waddell Immunolocalization of 11{beta}-Hydroxysteroid Dehydrogenase Types 1 and 2 in Rat Uterus: Variation Across the Estrous Cycle and Regulation by Estrogen and Progesterone Endocrinology, January 1, 1998; 139(1): 376 - 382. [Abstract] [Full Text] [PDF] |
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Y. Kotelevtsev, M. C. Holmes, A. Burchell, P. M. Houston, D. Schmoll, P. Jamieson, R. Best, R. Brown, C. R. W. Edwards, J. R. Seckl, et al. 11beta -Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress PNAS, December 23, 1997; 94(26): 14924 - 14929. [Abstract] [Full Text] [PDF] |
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P. Sinha, I. Halasz, J. F. Choi, R. F. McGivern, and E. Redei Maternal Adrenalectomy Eliminates a Surge of Plasma Dehydroepiandrosterone in the Mother and Attenuates the Prenatal Testosterone Surge in the Male Fetus Endocrinology, November 1, 1997; 138(11): 4792 - 4797. [Abstract] [Full Text] [PDF] |
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K. Sun, K. Yang, and J. R. G. Challis Differential Regulation of 11 {beta}-Hydroxysteroid Dehydrogenase Type 1 and 2 by Nitric Oxide in Cultured Human Placental Trophoblast and Chorionic Cell Preparation Endocrinology, November 1, 1997; 138(11): 4912 - 4920. [Abstract] [Full Text] [PDF] |
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R.-S. Ge, H.-B. Gao, V. L. Nacharaju, G. L. Gunsalus, and M. P. Hardy Identification of a Kinetically Distinct Activity of 11{beta}-Hydroxysteroid Dehydrogenase in Rat Leydig Cells Endocrinology, June 1, 1997; 138(6): 2435 - 2442. [Abstract] [Full Text] [PDF] |
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H.-B. Gao, R.-S. Ge, V. Lakshmi, A. Marandici, and M. P. Hardy Hormonal Regulation of Oxidative and Reductive Activities of 11{beta}-Hydroxysteroid Dehydrogenase in Rat Leydig Cells Endocrinology, January 1, 1997; 138(1): 156 - 161. [Abstract] [Full Text] [PDF] |
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L. J. S. Williams, V. Lyons, I. MacLeod, V. Rajan, G. J. Darlington, V. Poli, J. R. Seckl, and K. E. Chapman C/EBP Regulates Hepatic Transcription of 11beta -Hydroxysteroid Dehydrogenase Type 1. A NOVEL MECHANISM FOR CROSS-TALK BETWEEN THE C/EBP AND GLUCOCORTICOID SIGNALING PATHWAYS J. Biol. Chem., September 22, 2000; 275(39): 30232 - 30239. [Abstract] [Full Text] [PDF] |
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N. M. Morton, M. C. Holmes, C. Fievet, B. Staels, A. Tailleux, J. J. Mullins, and J. R. Seckl Improved Lipid and Lipoprotein Profile, Hepatic Insulin Sensitivity, and Glucose Tolerance in 11beta -Hydroxysteroid Dehydrogenase Type 1 Null Mice J. Biol. Chem., October 26, 2001; 276(44): 41293 - 41300. [Abstract] [Full Text] [PDF] |
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J. L. W. Yau, J. Noble, C. J. Kenyon, C. Hibberd, Y. Kotelevtsev, J. J. Mullins, and J. R. Seckl Lack of tissue glucocorticoid reactivation in 11beta -hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments PNAS, April 10, 2001; 98(8): 4716 - 4721. [Abstract] [Full Text] [PDF] |
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J. Hanafusa, T. Mune, T. Tanahashi, Y. Isomura, T. Suwa, M. Isaji, H. Daido, H. Morita, M. Murayama, and K. Yasuda Altered corticosteroid metabolism differentially affects pituitary corticotropin response Am J Physiol Endocrinol Metab, February 1, 2002; 282(2): E466 - E473. [Abstract] [Full Text] [PDF] |
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