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INVITED REVIEW

THE WALTER B. CANNON MEMORIAL AWARD LECTURE

Genetic manipulation of 11-hydroxysteroid dehydrogenases in mice

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom

11-Hydroxysteroid dehydrogenases (HSDs) interconvert active 11-hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11-keto derivatives (cortisone, 11-dehydrocorticosterone). 11-HSD type 1 is a predominant reductase that regenerates active glucocorticoids in expressing cells, thus amplifying local glucocorticoid action, whereas 11-HSD type 2 catalyzes rapid dehydrogenation, potently inactivating intracellular glucocorticoids. Both isozymes thus regulate receptor activation by substrate availability. Spatial and temporal regulation of expression are important determinants of the physiological roles of 11-HSDs, with each isozyme exhibiting a distinct, tissue-restricted pattern together with dynamic regulation during development and in response to environmental challenges, including diet and stress. Transgenic approaches in the mouse have contributed significantly toward an understanding of the importance of these prereceptor regulatory mechanisms on corticosteroid receptor activity and have highlighted its potential relevance to human health and disease. Here we discuss current ideas of the physiological roles of 11-HSDs, with emphasis on the key contributions made by studies of 11-HSD gene manipulation in vivo.

glucocorticoid; mineralocorticoid; steroid metabolism; tissue specific; transgenic

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