Comparative enzymology of 11beta-hydroxysteroid dehydrogenase type 1 from six species.

Arampatzis, Spyridon; Kadereit, Bert; Schuster, Daniela; Balazs, Zoltan; Schweizer, Roberto A S; Frey, Felix Julius; Langer, Thierry; Odermatt, Alexander (2005). Comparative enzymology of 11beta-hydroxysteroid dehydrogenase type 1 from six species. Journal of molecular endocrinology, 35(1), pp. 89-101. 10.1677/jme.1.01736

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension

UniBE Contributor:

Arampatzis, Spyridon; Balazs, Zoltan; Frey, Felix Julius and Odermatt, Alexander

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0952-5041

Language:

English

Submitter:

Spyridon Arampatzis

Date Deposited:

25 Sep 2014 12:21

Last Modified:

25 Sep 2014 12:21

Publisher DOI:

10.1677/jme.1.01736

PubMed ID:

16087724

URI:

https://boris.unibe.ch/id/eprint/51884

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