11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.

Abstract

11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-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 "11beta-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 11beta-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 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.

• Authors: Jeremy W Tomlinson, Elizabeth A Walker, Iwona J Bujalska, Nicole Draper, Gareth G Lavery, Mark S Cooper, Martin Hewison, Paul M Stewart
• Journal: Endocrine reviews (Endocr Rev) Vol. 25 Issue 5 Pg. 831-66 (Oct 2004) ISSN: 0163-769X [Print] United States
• PMID: 15466942 (Publication Type: Journal Article, Review)

Chemical References

• Enzyme Inhibitors
• Glucocorticoids
• Recombinant Proteins
• NADP
• Carbohydrate Dehydrogenases
• galactose-6-phosphate dehydrogenase
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Cortisone Reductase
• Hydrocortisone

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors, chemistry, genetics, physiology)
• Amino Acid Sequence
• Animals
• Carbohydrate Dehydrogenases (genetics)
• Cloning, Molecular
• Cortisone Reductase (deficiency, genetics)
• Enzyme Inhibitors
• Gene Expression Regulation, Enzymologic
• Glaucoma (enzymology)
• Glucocorticoids (pharmacology)
• Humans
• Hydrocortisone (metabolism)
• Molecular Sequence Data
• Mutation
• NADP (metabolism)
• Obesity (enzymology)
• Organ Specificity
• Osteoporosis (enzymology)
• Recombinant Proteins
• Sequence Alignment
• Substrate Specificity
• Transcription, Genetic