Substrate and inhibitor specificity of the cloned human 11 beta-hydroxysteroid dehydrogenase type 2 isoform.
The 11 beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme is thought to confer specificity on the mineralocorticoid receptor by inactivating glucocorticoids in mineralocorticoid target organs. The cloned 11 beta HSD2 displayed Michaelis constant values for corticosterone and cortisol of 5.1 and 61 nM, respectively. Linearity in the dose-response curve ranged between 1 and 200 nM for corticosterone and 25 and 2,000 nM for cortisol, with no evidence for complex kinetics. Inhibition of cortisol oxidation by other steroids was purely competitive in nature. Inhibition of 11 beta HSD2 activity by the end product or aldosterone occurred only at supraphysiological levels, whereas corticosterone and deoxycorticosterone displayed significant inhibition at physiological concentrations and progesterone at concentrations that occur during pregnancy. In intact transfected CHOP cells, dexamethasone was converted to 11-dehydrodexamethasone by 11 beta HSD2 but not type 1 11 beta-hydroxysteroid dehydrogenase, an aspect that may be useful in evaluating 11 beta HSD activity in intact cells.
Ferrari
P
P
Baker Medical Research Institute, Melbourne, Australia.
Smith
R E
RE
Funder
J W
JW
Krozowski
Z S
ZS
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D003345:Corticosterone / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000494:pharmacology; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology; D013379:Substrate Specificity
D007527:Isoenzymes; D011374:Progesterone; D003907:Dexamethasone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D003345:Corticosterone; D006854:Hydrocortisone