Regulation of 11 beta-hydroxysteroid dehydrogenase activity by the hypothalamic-pituitary-adrenal axis in the rat.
11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) inactivates glucocorticoids and thereby modulates their access to both mineralocorticoid and glucocorticoid receptors. Since 11 beta-OHSD activity influences the biological responses of the hypothalamic-pituitary-adrenal axis, it might be regulated by components of this axis. We examined 11 beta-OHSD activity in adrenalectomized rats treated for 9 days with dexamethasone and with or without ACTH. Adrenalectomy and low-dose (2 micrograms/day) dexamethasone had no effect on 11 beta-OHSD activity in renal cortex, hippocampus or heart, and reduced enzyme activity in aorta. High-dose dexamethasone (50 micrograms/day) had no effect in renal cortex but increased enzyme activity by at least 50% in all other sites. This effect of dexamethasone was unaffected by the co-administration of ACTH. We also examined the metabolism of dexamethasone by 11 beta-OHSD in homogenized rat tissues. Only in kidney, in the presence of NAD rather than NADP, was dexamethasone converted to a more polar metabolite previously identified as 11-dehydrodexamethasone. We conclude that: dexamethasone induction of 11 beta-OHSD is tissue-specific, and includes vascular tissues and hippocampus but not kidney; this tissue-specificity may be explained by contrasting metabolism of dexamethasone by the isoforms of 11 beta-OHSD; fluctuations of glucocorticoid levels within the physiological range may not have a biologically significant effect on 11 beta-OHSD activity; and the inhibitory effect of ACTH, observed previously in humans, is likely to depend on the presence of intact adrenal glands.
Walker
B R
BR
Department of Medicine, Western General Hospital, University of Edinburgh, UK.
Williams
B C
BC
Edwards
C R
CR
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000201:enzymology; D046508:Culture Techniques; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation; D006624:Hippocampus / Q000201:enzymology; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007527:Isoenzymes; D007668:Kidney / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D009243:NAD / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D007527:Isoenzymes; D009243:NAD; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases