Recycling between cortisol and cortisone in human splanchnic, subcutaneous adipose, and skeletal muscle tissues in vivo.
Recycling between cortisol and cortisone in human splanchnic, subcutaneous adipose, and skeletal muscle tissues in vivo.
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作者：
Hughes KA;Manolopoulos KN;Iqbal J;Cruden NL;Stimson RH;Reynolds RM;Newby DE;Andrew R;Karpe F;Walker BR
11β-羟基类固醇脱氢酶 1 型 (11βHSD1) 是代谢综合征的治疗靶点，因为它催化脂肪和肝脏中的可的松还原为皮质醇。 11βHSD1 还可以在体外催化逆脱氢酶反应（例如，如果辅因子有限）。我们使用稳定同位素示踪剂来检验 11βHSD1 还原酶和 11βHSD1 脱氢酶活性均存在于人体体内代谢组织中的假设。 1,2-[2H]2-可的松（d2-可的松）经验证可作为 11β-脱氢酶活性及其受甘草抑制的示踪剂。将 d2-可的松和 9,11,12,12-[2H]4-皮质醇 (d4-皮质醇)（用于测量 11β-还原酶活性）混合，并从骨骼肌、皮下脂肪 (n = 6) 和肝脏 (n = 4) 获取静脉样本。通过液相色谱-串联质谱法测量类固醇，并根据血流调整动静脉差异。数据为平均值±SEM。在肌肉（皮质醇释放 19.7 ± 4.1 pmol/100 mL/min，d3-皮质醇 5.9 ± 1.8 pmol/100 mL/min，可的松 15.2 ± 5.8 pmol/100 mL/min）和内脏（皮质醇 64.0 ± 11.4）中检测到 11β-还原酶和 β-脱氢酶活性nmol/min、d3-皮质醇 12.9 ± 2.1 nmol/min 和可的松 19.5 ± 2.8 nmol/min) 循环。在脂肪中，脱氢酶比还原酶更容易检测到（可的松释放量 38.7 ± 5.8 pmol/100 g/min）。体内代谢组织中皮质醇和可的松之间的主动循环可能有助于细胞内皮质醇的动态控制，但使肥胖和糖尿病中 11βHSD1 转录失调的后果变得不可预测。 11βHSD1 抑制剂在 II 期研究中的功效令人失望，可以解释为缺乏对 11β-还原酶的选择性。
11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) is a therapeutic target in metabolic syndrome because it catalyses reductase regeneration of cortisol from cortisone in adipose and liver. 11βHSD1 can also catalyze the reverse dehydrogenase reaction in vitro (e.g., if cofactor is limited). We used stable isotope tracers to test the hypothesis that both 11βHSD1-reductase and -dehydrogenase activities occur in human metabolic tissues in vivo. 1,2-[2H]2-Cortisone (d2-cortisone) was validated as a tracer for 11β-dehydrogenase activity and its inhibition by licorice. d2-Cortisone and 9,11,12,12-[2H]4-cortisol (d4-cortisol) (to measure 11β-reductase activity) were coinfused and venous samples obtained from skeletal muscle, subcutaneous adipose (n = 6), and liver (n = 4). Steroids were measured by liquid chromatography–tandem mass spectrometry and arteriovenous differences adjusted for blood flow. Data are means ± SEM. 11β-Reductase and -dehydrogenase activities were detected in muscle (cortisol release 19.7 ± 4.1 pmol/100 mL/min, d3-cortisol 5.9 ± 1.8 pmol/100 mL/min, and cortisone 15.2 ± 5.8 pmol/100 mL/min) and splanchnic (cortisol 64.0 ± 11.4 nmol/min, d3-cortisol 12.9 ± 2.1 nmol/min, and cortisone 19.5 ± 2.8 nmol/min) circulations. In adipose, dehydrogenase was more readily detected than reductase (cortisone release 38.7 ± 5.8 pmol/100 g/min). Active recycling between cortisol and cortisone in metabolic tissues in vivo may facilitate dynamic control of intracellular cortisol but makes consequences of dysregulation of 11βHSD1 transcription in obesity and diabetes unpredictable. Disappointing efficacy of 11βHSD1 inhibitors in phase II studies could be explained by lack of selectivity for 11β-reductase.
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影响因子：
5.8
作者：
Andrew, R;Smith, K;Walker, BR
通讯作者：
Walker, BR
DOI：
10.1038/oby.2004.3
发表时间：
2004-01-01
期刊：
OBESITY RESEARCH
影响因子：
--
作者：
Engeli, S;Böhnke, J;Sharma, AM
通讯作者：
Sharma, AM
影响因子：
7.7
作者：
Andrew, R;Westerbacka, J;Walker, BR
通讯作者：
Walker, BR
影响因子：
6.9
作者：
Lee, Mi-Jeong;Fried, Susan K.;Hermanowski-Vosatka, Anne
通讯作者：
Hermanowski-Vosatka, Anne
影响因子：
3.2
作者：
Best, R;Walker, BR
通讯作者：
Walker, BR