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

Department of Endocrinology, Diabetes, and Nutrition, Klinikum Benjamin Franklin, Freie Universität Berlin (S.D., E.E., P.B., M.Q., C.B.-V., M.R., W.O., V.B.), and Research Laboratories of Schering AG (D.S., P. E.), 12200 Berlin, Germany

Address all correspondence and requests for reprints to: Dr. Sven Diederich, Department of Endocrinology, Diabetes, and Nutrition, Klinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail: diederich{at}ukbf.fu-berlin.de.

Abstract

The 11ß-hydroxysteroid dehydrogenase (11ß-HSD) system plays a pivotal role in glucocorticoid (GC) and mineralocorticoid (MC) action. Although 11ß-HSD activities are important determinants for the efficacy of synthetic MCs and GCs, corresponding pharmacokinetic data are scanty. Therefore, we characterized 11ß-HSD profiles for a wide range of steroids often used in clinical practice. 11ß-HSD1 and 11ß-HSD2 were selectively examined in 1) human liver and kidney cortex microsomes, and 2) Chinese hamster ovarian cells stably transfected with 11ß-HSD1 or 11ß-HSD2 expression vectors. Both systems produced concordant evidence for the following conclusions.

Oxidation of steroids by 11ß-HSD2 is diminished if they are fluorinated in position 6 or 9 (e.g. in dexamethasone) or methylated at 2 or 6 (in methylprednisolone) or 16 or 16ß, 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 9-fluorocortisol and should be considered in GC therapy directed to 11ß-HSD2-expressing tissues (kidney, colon, and placentofetal unit). 11ß-HSD2 oxidation of prednisolone is more effective than that of cortisol, explaining the reduced MC activity of prednisolone compared with cortisol.

Reduction by 11ß-HSD1 is diminished by 16-methyl, 16ß-methyl, 2-methyl, and 2-chlor substitution, whereas it is increased by the 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 11ßHSDs may be essential for an optimized steroid therapy.

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