The cortisol-cortisone shuttle and the apparent specificity of glucocorticoid and mineralocorticoid receptors.
In vitro studies on both the purified cytosolic mineralocorticoid receptor (MR) and the recombinant expressed human MR have shown that it is non-specific and does not distinguish between cortisol and aldosterone. These contrast with the apparent in vivo selectivity of the MR in tissues such as the kidney for aldosterone in preference to cortisol despite the 100-fold molar excess of cortisol. This review gives the evidence that indicates that 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), the enzyme responsible for the interconversion of cortisol and inactive cortisone, acts as a protective mechanism for the MR. In aldosterone-selective tissues it shuttles cortisol to cortisone and thus prevents glucocorticoid access. Aldosterone itself is not a substrate for the enzyme. The current data suggest that this is an autocrine system with both the enzyme and the MR present within the same cell. In certain tissues such as the kidney there may also be additional upstream steroid metabolism indicating a paracrine system. Lack of this protective system results in cortisol acting as a potent mineralocorticoid. This may be congenital as in the apparent mineralocorticoid excess syndrome or acquired secondary to liquorice-induced inhibition of 11 beta-OHSD. In addition to its role in MR protection 11 beta-OHSD may also be important in modulating steroid access to glucocorticoid receptors. The ontogeny of the enzyme in the testis and the brain suggests that its tissue-specific control may be crucial in allowing normal development.
Edwards
C R
CR
Department of Medicine, Western General Hospital, Edinburgh, Scotland.
Stewart
P M
PM
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D003348:Cortisone / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019695:Glycyrrhizic Acid; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D006913:Hydroxysteroid Dehydrogenases / Q000502:physiology; D007150:Immunohistochemistry; D007668:Kidney / Q000737:chemistry / Q000187:drug effects; D008901:Mineralocorticoids / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D001743:Urinary Bladder / Q000737:chemistry / Q000187:drug effects / Q000502:physiology
D008901:Mineralocorticoids; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D019695:Glycyrrhizic Acid; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D006034:Glycyrrhetinic Acid; D003348:Cortisone; D006854:Hydrocortisone