Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Queen's Medical Research Institute, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
Br J Pharmacol. 2021 Aug;178(16):3309-3326. doi: 10.1111/bph.15367. Epub 2021 Feb 4.
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.
Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.
The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.
The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.
This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
11β-羟甾类脱氢酶 1（11β-HSD1）调节组织特异性糖皮质激素代谢，其表达和活性受损与多种疾病有关。抑制 11β-HSD1 的活性被认为是一种很有前途的治疗策略。本研究旨在探讨 11β-HSD1 的替代 7-氧代胆酸底物或其与 7-羟基产物的比值是否可以作为酶活性降低的生物标志物。
通过超高效液相色谱串联质谱法在四种不同的 11β-HSD1 活性降低的小鼠模型（全身 11KO 和肝脏特异性 11β-HSD1 敲除小鼠 11LKO、缺乏提供 11β-HSD1 辅因子 NADPH 的己糖-6-磷酸脱氢酶（H6pdKO）和用药理学抑制剂 carbenoxolone 处理的小鼠）的血浆和肝组织样本中测量胆汁酸谱。此外，还评估了 H6pdKO 和 carbenoxolone 处理的小鼠中 11β-HSD1 的表达和活性。
由于胆汁酸浓度的个体间差异较大，酶产物与底物的比值比绝对水平更能可靠地反映 11β-HSD1 的活性。四种小鼠模型的血浆和肝组织中 7β-羟基化的熊脱氧胆酰牛磺酸（UDC-Tau）与 7-氧代胆酰牛磺酸（7oxoLC-Tau）的比值均降低，在 H6pdKO 和 carbenoxolone 处理的 11β-HSD1 活性中度降低的小鼠中也降低。在 H6PD 丧失的情况下，11β-HSD1 的氧化还原活性仍然存在，这表明内质网中存在替代的 NADPH 来源。
血浆 UDC-Tau/7oxo-LC-Tau 比值可检测不同小鼠模型中 11β-HSD1 的氧化还原活性降低。该比值可能是病理生理情况下或药物抑制时 11β-HSD1 活性降低的有用生物标志物。
本文是关于氧化固醇、终身健康和治疗的专题问题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
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