Arampatzis Spyridon, Kadereit Bert, Schuster Daniela, Balazs Zoltan, Schweizer Roberto A S, Frey Felix J, Langer Thierry, Odermatt Alex
Division of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland.
J Mol Endocrinol. 2005 Aug;35(1):89-101. doi: 10.1677/jme.1.01736.
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.
11β-羟基类固醇脱氢酶1型（11β-HSD1）催化可的松在细胞内转化为皮质醇，目前被认为是治疗代谢综合征患者的一个有前景的靶点；因此，人们对开发选择性抑制剂有着浓厚的兴趣。对于此类抑制剂的临床前测试，必须了解常用物种中11β-HSD1的特性。因此，我们测定了六种物种的11β-HSD1在底物亲和力和抑制剂作用方面的差异。11β-HSD1对可的松和11-脱氢皮质酮的催化活性差异相当小。人、仓鼠和豚鼠的11β-HSD1在可的松的氧化还原反应中表现出最高的催化效率，而小鼠和大鼠的活性居中，犬的活性最低。小鼠的11β-HSD1最有效地还原11-脱氢皮质酮，而犬的该酶活性低于其他物种。除仓鼠外，所有分析物种的重组11β-HSD1均可将7-酮胆固醇（7KC）立体定向转化为7β-羟基胆固醇，仓鼠则略微倾向于形成7α-羟基胆固醇。重要的是，豚鼠和犬的11β-HSD1表现出非常低的7-氧化还原酶活性。此外，我们证明了包括内源性化合物、天然化学物质和药物化合物在内的各种11β-HSD1抑制剂的效力存在显著的物种特异性差异。结果表明11β-HSD1疏水底物结合口袋的三维结构存在显著差异，并强调在解释不同动物实验结果时必须考虑物种特异性差异。通过基于细胞的测试系统评估此类差异，可能有助于选择合适的动物用于新型潜在药物候选物的安全性和有效性研究。
