title: Comparative enzymology of 11beta-hydroxysteroid dehydrogenase type 1 from six species.
abstract: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-HSD1 from the commonly used species have to be known. Therefore, we determined differences in substrate affinity and inhibitor effects for 11beta-HSD1 from six species. The differences in catalytic activities with cortisone and 11-dehydrocorticosterone were rather modest. Human, hamster and guinea-pig 11beta-HSD1 displayed the highest catalytic efficiency in the oxoreduction of cortisone, while mouse and rat showed intermediate and dog the lowest activity. Murine 11beta-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 7beta-hydroxycholesterol by recombinant 11beta-HSD1 from all species analyzed except hamster, which showed a slight preference for the formation of 7alpha-hydroxycholesterol. Importantly, guinea-pig and canine 11beta-HSD1 displayed very low 7-oxoreductase activities. Furthermore, we demonstrate significant species-specific variability in the potency of various 11beta-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 11beta-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.
authors.affiliation: Division of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Arampatzis
authors.forename: Bert
authors.initials: B
authors.lastname: Kadereit
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Balazs
authors.forename: Roberto A S
authors.initials: RA
authors.lastname: Schweizer
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Frey
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain; D002460:Cell Line; D003001:Cloning, Molecular; D003345:Corticosterone / Q000031:analogs & derivatives / Q000378:metabolism; D003348:Cortisone / Q000378:metabolism; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C003552:11-dehydrocorticosterone; D003348:Cortisone; D003345:Corticosterone