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Endocrinology, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom
Correspondence: Address all correspondence and requests for reprints to: Paul M. Stewart, M.D., FRCP FMedSci, Professor of Medicine, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, B15 2TH, United Kingdom. E-mail: p.m.stewart{at}bham.ac.uk
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11ß-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11ß-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11ß-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11ß-HSD1 activity. Therapeutic inhibition of 11ß-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
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I. J Bujalska, O. M Durrani, J. Abbott, C. U Onyimba, P. Khosla, A. H Moosavi, T. T Q Reuser, P. M Stewart, J. W Tomlinson, E. A Walker, et al. Characterisation of 11{beta}-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat J. Endocrinol., February 1, 2007; 192(2): 279 - 288. [Abstract] [Full Text] [PDF]
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M. Corton, J. I. Botella-Carretero, A. Benguria, G. Villuendas, A. Zaballos, J. L. San Millan, H. F. Escobar-Morreale, and B. Peral Differential Gene Expression Profile in Omental Adipose Tissue in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 328 - 337. [Abstract] [Full Text] [PDF]
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B. R WALKER and R. ANDREW Tissue Production of Cortisol by 11beta-Hydroxysteroid Dehydrogenase Type 1 and Metabolic Disease Ann. N.Y. Acad. Sci., November 1, 2006; 1083(1): 165 - 184. [Abstract] [Full Text] [PDF]
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D. J. Wake, N. Z. M. Homer, R. Andrew, and B. R. Walker Acute In Vivo Regulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity by Insulin and Intralipid Infusions in Humans J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4682 - 4688. [Abstract] [Full Text] [PDF]
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 J. L. Turgeon, M. C. Carr, P. M. Maki, M. E. Mendelsohn, and P. M. Wise Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies Endocr. Rev., October 1, 2006; 27(6): 575 - 605. [Abstract] [Full Text] [PDF]
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S. Y. Kim, A. D. Nguyen, J.-L. Gao, P. M. Murphy, B. C. Mansfield, and J. Y. Chou Bone Marrow-derived Cells Require a Functional Glucose 6-Phosphate Transporter for Normal Myeloid Functions J. Biol. Chem., September 29, 2006; 281(39): 28794 - 28801. [Abstract] [Full Text] [PDF]
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B. Mariniello, V. Ronconi, S. Rilli, P. Bernante, M. Boscaro, F. Mantero, and G. Giacchetti Adipose tissue 11{beta}-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing's syndrome Eur. J. Endocrinol., September 1, 2006; 155(3): 435 - 441. [Abstract] [Full Text] [PDF]
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C. U Onyimba, N. Vijapurapu, S J. Curnow, P. Khosla, P. M Stewart, P. I Murray, E. A Walker, and S. Rauz Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye. J. Endocrinol., August 1, 2006; 190(2): 483 - 493. [Abstract] [Full Text] [PDF]
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A. Gambineri, V. Vicennati, S. Genghini, F. Tomassoni, U. Pagotto, R. Pasquali, and B. R. Walker Genetic Variation in 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Predicts Adrenal Hyperandrogenism among Lean Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2295 - 2302. [Abstract] [Full Text] [PDF]
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W. Li, L. Gao, Y. Wang, T. Duan, L. Myatt, and K. Sun Enhancement of Cortisol-Induced 11{beta}-Hydroxysteroid dehydrogenase Type 1 Expression by Interleukin 1{beta} in Cultured Human Chorionic Trophoblast Cells Endocrinology, May 1, 2006; 147(5): 2490 - 2495. [Abstract] [Full Text] [PDF]
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J. A. Shoener, R. Baig, and K. C. Page Prenatal exposure to dexamethasone alters hippocampal drive on hypothalamic-pituitary-adrenal axis activity in adult male rats Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2006; 290(5): R1366 - R1373. [Abstract] [Full Text] [PDF]
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G. G. Lavery, E. A. Walker, N. Draper, P. Jeyasuria, J. Marcos, C. H. L. Shackleton, K. L. Parker, P. C. White, and P. M. Stewart Hexose-6-phosphate Dehydrogenase Knock-out Mice Lack 11beta-Hydroxysteroid Dehydrogenase Type 1-mediated Glucocorticoid Generation J. Biol. Chem., March 10, 2006; 281(10): 6546 - 6551. [Abstract] [Full Text] [PDF]
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R. S. Chriguer, L. L. K. Elias, I. M. da Silva Jr., J. G. H. Vieira, A. C. Moreira, and M. de Castro Glucocorticoid Sensitivity in Young Healthy Individuals: in Vitro and in Vivo Studies J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5978 - 5984. [Abstract] [Full Text] [PDF]
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P. C. White Genotypes at 11{beta}-Hydroxysteroid Dehydrogenase Type 11B1 and Hexose-6-Phosphate Dehydrogenase Loci Are Not Risk Factors for Apparent Cortisone Reductase Deficiency in a Large Population-Based Sample J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5880 - 5883. [Abstract] [Full Text] [PDF]
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C. van Kooten and A. M. Woltman CD40 brings the shuttle down Blood, September 15, 2005; 106(6): 1895 - 1896. [Full Text] [PDF]
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L. Freeman, M. Hewison, S. V. Hughes, K. N. Evans, D. Hardie, T. K. Means, and R. Chakraverty Expression of 11{beta}-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells Blood, September 15, 2005; 106(6): 2042 - 2049. [Abstract] [Full Text] [PDF]
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 R. S. Weinstein 11{beta}-HSD: Guardian or Gate Crasher? IBMS BoneKEy, September 1, 2005; 2(9): 6 - 13. [Full Text] [PDF]
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J. L. San Millan, J. I. Botella-Carretero, F. Alvarez-Blasco, M. Luque-Ramirez, J. Sancho, P. Moghetti, and H. F. Escobar-Morreale A Study of the Hexose-6-Phosphate Dehydrogenase Gene R453Q and 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Gene 83557insA Polymorphisms in the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4157 - 4162. [Abstract] [Full Text] [PDF]
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F. Hammer, S. Subtil, P. Lux, C. Maser-Gluth, P. M. Stewart, B. Allolio, and W. Arlt No Evidence for Hepatic Conversion of Dehydroepiandrosterone (DHEA) Sulfate to DHEA: In Vivo and in Vitro Studies J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3600 - 3605. [Abstract] [Full Text] [PDF]
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A. K. Agarwal and R. J. Auchus Minireview: Cellular Redox State Regulates Hydroxysteroid Dehydrogenase Activity and Intracellular Hormone Potency Endocrinology, June 1, 2005; 146(6): 2531 - 2538. [Abstract] [Full Text] [PDF]
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E. Seeman and G. J. Strewler Clinical and Basic Research Papers - August 2004 Selections IBMS BoneKEy, October 1, 2004; 1(10): 1 - 3. [Full Text] [PDF]
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