Inactivation of 11β-hydroxysteroid dehydrogenase type 1 by gene targeting in mice

Y. V. Kotelevtsev, P. M. Jamieson, R. Best, F. Stewart, C. R.W. Edwards, J. R. Seckl, J. J. Mullins

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6 Citations (Scopus)

Abstract

11β-Hydroxysteroid dehydrogenase (11β-HSD) catalyses the inter- conversion of corticosterone and inert 11-dehydrocorticosterone. The NADP(H)-dependent type 1 isozyme is widely distributed and acts predominantly as a reductase in vivo, regenerating active glucocorticoid (1). In contrast, 11β-HSD-2 is a higher-affinity, NAD-dependent, exclusive dehydrogenase, with expression limited to mineralocorticoid target tissues (kidney, colon, parotid) and placenta(2). Gene targeting of 11β-HSD-1 was accomplished in the mouse 129/Sv embryonic stem cell line CGR 8. A chimera transmitting the mutation into the germ line was successfully obtained. Animals homozygous for the targeted allele were produced by the subsequent breeding of heterozygotes. Mice homozygous for targeted 11β-HSD-1 were viable, of normal birth weight and postnatal growth and did not have major visible abnormalities. 11β-HSD type 1 activity was undetectable in liver, brain and lung in homozygous 'knock out' mice. No 11β-HSD-1 mRNA expression was detected in these organs. Proportional reduction of 11β-HSD-1 mRNA expression and enzyme activity was observed in heterozygotes. Homozygous males and females were fertile. Knock out mice had lower glucose levels on starvation. Preliminary findings in homozygous 11β-HSD-1 knockout mice suggest they show adrenocortical hyperplasia presumably reflecting loss of hepatic reactivation of glucocorticoids. These mice will be useful in dissection of the physiological roles of 11β-HSD-1.

Original languageEnglish
Pages (from-to)791-792
Number of pages2
JournalEndocrine Research
Volume22
Issue number4
DOIs
Publication statusPublished - 1996
Externally publishedYes

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