11β-Hydroxysteroid Dehydrogenase Types 1 and 2: An Important Pharmacokinetic Determinant for the Activity of Synthetic Mineralo- and Glucocorticoids

Abstract

The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) system plays a pivotal role in glucocorticoid (GC) and mineralocorticoid (MC) action. Although 11beta-HSD activities are important determinants for the efficacy of synthetic MCs and GCs, corresponding pharmacokinetic data are scanty. Therefore, we characterized 11beta-HSD profiles for a wide range of steroids often used in clinical practice. 11beta-HSD1 and 11beta-HSD2 were selectively examined in 1) human liver and kidney cortex microsomes, and 2) Chinese hamster ovarian cells stably transfected with 11beta-HSD1 or 11beta-HSD2 expression vectors. Both systems produced concordant evidence for the following conclusions. Oxidation of steroids by 11beta-HSD2 is diminished if they are fluorinated in position 6alpha or 9alpha (e.g. in dexamethasone) or methylated at 2alpha or 6alpha (in methylprednisolone) or 16alpha or 16beta, by a methylene group at 16 (in prednylidene), methyloxazoline at 16, 17 (in deflazacort), or a 2-chlor configuration. Whereas the methyl groups also decrease reductase activity (steric effects), fluorination increases reductase activity (negative inductive effect), leading to a shift to reductase activity. This may explain the strong MC activity of 9alpha-fluorocortisol and should be considered in GC therapy directed to 11beta-HSD2-expressing tissues (kidney, colon, and placentofetal unit). 11beta-HSD2 oxidation of prednisolone is more effective than that of cortisol, explaining the reduced MC activity of prednisolone compared with cortisol. Reduction by 11beta-HSD1 is diminished by 16alpha-methyl, 16beta-methyl, 2alpha-methyl, and 2-chlor substitution, whereas it is increased by the Delta(1)-dehydro configuration in prednisone, resulting in higher hepatic first pass activation of prednisone compared with cortisone. To characterize a GC or a MC as substrate for the different 11betaHSDs may be essential for an optimized steroid therapy.

Expression of 11β-hydroxysteroid dehydrogenase enzymes in human osteosarcoma: potential role in pathogenesis and as targets for treatments

“…Although we have evaluated DHD, it is possible that structurally related synthetic glucocorticoids could be generated that have even greater ability to be activated powerfully and selectively by the 11b-HSD2 enzyme. Previous reports have analysed some of the structural determinants that determine directionality of glucocorticoid conversion by the 11b-HSD enzymes (Diederich et al 2002) and this should facilitate development of additional glucocorticoids.…”

“…Although 11b-HSD2 activity is unidirectional for endogenous glucocorticoids, several studies have demonstrated that the substitution of a fluoride molecule at the 9a position of the glucocorticoid structure (as seen in dexamethasone (DEX)) dramatically affects the way the enzyme metabolises these steroids (Diederich et al 2002). 9a-Fluorinated steroids are less effectively oxidised (inactivated) but in addition their inactive counterparts can be reduced (converted to their active form) by the 11b-HSD2 enzyme.…”

Antenatal Dexamethasone Treatment Leads to Changes in Gene Expression in a Murine Late Placenta

“…11β-HSD1 is a low-affinity reduced NADP(H)-dependent dehydrogenase-oxoreductase which is expressed in glucocorticoid responsive tissues and activates cortisone to cortisol locally. In contrast 11β-HSD2 which is a high-affinity NAD + -dependent unidirectional dehydrogenase converts cortisol into its inactive metabolite cortisone and also inactivates prednisolone in a similar fashion [14,15]. 11β-HSD2 is highly expressed in human and murine placenta throughout gestation [16,17].…”

Decreased hydrocortisone sensitivity of T cell function in multiple sclerosis-associated major depression

“…We found group differences for hydrocortisone, which can be inactivated by the enzyme 11b-hydroxysteroid dehydrogenase 2 (11b-HSD2), but not dexamethasone, a weak 11b-HSD substrate (Diederich et al, 2002). The enzymes 11b-HSD1 and 2 play a pivotal role for local, tissue-specific regulation of steroid effects (Tomlinson et al, 2004) and are expressed in the immune system (Chapman et al, 2009).…”