HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (21) Citing Articles via Google Scholar Google Scholar Articles by Arampatzis, S. Articles by Odermatt, A. Search for Related Content PubMed PubMed Citation Articles by Arampatzis, S. Articles by Odermatt, A.

Division of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland
¹ Institute of Pharmacy, University of Innsbruck, Innrain 52, A-6020 Innsbruck, Austria

(Requests for offprints should be addressed to A Odermatt; Email: alex.odermatt{at}dkf.unibe.ch)

^* (S Arampatzis and B Kadereit contributed equally to the present study)

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1), catalyzing the intracellular activation of cortisone to cortisol, is currently considered a promising target to treat patients with metabolic syndrome; hence, there is considerable interest in the development of selective inhibitors. For preclinical tests of such inhibitors, the characteristics of 11ß-HSD1 from the commonly used species have to be known. Therefore, we determined differences in substrate affinity and inhibitor effects for 11ß-HSD1 from six species. The differences in catalytic activities with cortisone and 11-dehydrocorticosterone were rather modest. Human, hamster and guinea-pig 11ß-HSD1 displayed the highest catalytic efficiency in the oxoreduction of cortisone, while mouse and rat showed intermediate and dog the lowest activity. Murine 11ß-HSD1 most efficiently reduced 11-dehydrocorticosterone, while the enzyme from dog showed lower activity than those from the other species. 7-Ketocholesterol (7KC) was stereospecifically converted to 7ß-hydroxycholesterol by recombinant 11ß-HSD1 from all species analyzed except hamster, which showed a slight preference for the formation of 7-hydroxycholesterol. Importantly, guinea-pig and canine 11ß-HSD1 displayed very low 7-oxoreductase activities. Furthermore, we demonstrate significant species-specific variability in the potency of various 11ß-HSD1 inhibitors, including endogenous compounds, natural chemicals and pharmaceutical compounds. The results suggest significant differences in the three-dimensional organization of the hydrophobic substrate-binding pocket of 11ß-HSD1, and they emphasize that species-specific variability must be considered in the interpretation of results obtained from different animal experiments. The assessment of such differences, by cell-based test systems, may help to choose the appropriate animal for safety and efficacy studies of novel potential drug candidates.

This article has been cited by other articles:

				E. M. Aubry and A. Odermatt Retinoic Acid Reduces Glucocorticoid Sensitivity in C2C12 Myotubes by Decreasing 11{beta}-Hydroxysteroid Dehydrogenase Type 1 and Glucocorticoid Receptor Activities Endocrinology, June 1, 2009; 150(6): 2700 - 2708. [Abstract] [Full Text] [PDF]

				I. D. Ignatova, R. M. Kostadinova, C. E. Goldring, A. R. Nawrocki, F. J. Frey, and B. M. Frey Tumor necrosis factor-{alpha} upregulates 11{beta}-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-{beta} in HepG2 cells Am J Physiol Endocrinol Metab, February 1, 2009; 296(2): E367 - E377. [Abstract] [Full Text] [PDF]

				P. Marcolongo, S. Piccirella, S. Senesi, L. Wunderlich, I. Gerin, J. Mandl, R. Fulceri, G. Banhegyi, and A. Benedetti The Glucose-6-Phosphate Transporter-Hexose-6-Phosphate Dehydrogenase-11{beta}-Hydroxysteroid Dehydrogenase Type 1 System of the Adipose Tissue Endocrinology, May 1, 2007; 148(5): 2487 - 2495. [Abstract] [Full Text] [PDF]