牛磺熊去氧胆酸性质、用途与生产工艺
牛磺熊去氧胆酸(tauroursodeoxycholicacid)是熊胆汁的主要有效成分，也是人工合成熊胆的主要成分，广泛存在于人和多种动物胆汁中的一种结合型胆汁酸，有着多种生理药理作用，该药及其制剂在国外已有二十年的上市临床经验，主要用于固醇性胆囊结石、胆汁郁积性肝病(如：原发性胆汁性肝硬化)、胆汁反流性胃炎、自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、慢性肝炎(乙肝、丙肝等)、酒精性脂肪肝、非酒精性脂肪肝、药物性肝损害、肝移植术前后预防及治疗并发症等。
牛磺熊去氧胆酸具有解痉、抗惊厥、抗炎及溶胆石等作用，临床主要用于治疗胆囊胆固醇结石、原发硬化性胆管炎、原发胆汁性肝硬化和慢性丙型病毒性肝炎等。
牛熊去氧胆酸钠又称牛磺熊去氧胆酸、牛磺熊脱氧胆酸，化学名称为3α，7β二羟基胆烷酰-N-牛磺酸，主要是存在于黑熊胆汁中，是熊胆中标志性有效成分。具有解痉、抗惊厥、抗炎及溶胆石等作用。
现代合成药物牛磺熊去氧胆酸，是由熊去氧胆酸的梭基与牛磺酸的氨基之间缩水而成的结合型胆汁酸。国外牛磺熊去氧胆酸胶囊已经上市，2007年作为进口药品获准在中国销售，临床主要用于治疗胆囊胆固醇结石、原发硬化性胆管炎、原发胆汁性肝硬化和慢性丙型病毒性肝炎等。目前牛磺熊去氧胆酸原料药及其制剂在中国还没有药品注册。
牛熊去氧胆酸钠是从熊胆汁中分离出来一种天然胆汁酸，属化学制剂，在体内与牛磺酸结合存在于胆汁中，是一种亲水性胆酸，为一种胆固醇结石溶解剂。能减少肝脏对胆固醇的分泌，降低胆汁中胆固醇的饱和度，促进胆汁酸的分泌，增加胆固醇在胆汁中的溶解度，使胆固醇结石溶解或防止结石的形成。可增加胆汁分泌量，松弛胆管口括约肌产生利胆作用，有利于结石的排出。本品不能溶解其他类型的胆结石。适用于治疗胆固醇性结石、高脂血症、胆汁分泌障碍性疾病、原发性胆汁性肝硬化、慢性肝炎、胆汁反流性胃炎和预防肝移植急性排斥及反应。本品的溶石作用略弱于鹅去氧胆酸。
以上信息由Chemicalbook的Andy编辑整理。
1)牛磺熊去氧胆酸粗品的制备，按以下步骤进行：
在反应釜中，加入4.0KG熊去氧胆酸，加入19KG丙酮，搅拌下加入三乙胺1650ml，开启夹套制冷，将混合液的温度降至-10℃。流加氯甲酸乙酯1120ml，控制氯甲酸乙酯的加入速度，使得反应液温度维持在-5-0℃之间，30分钟时加完，继续维持温度搅拌反应40分钟，制得熊去氧胆酸与氯甲酸乙酯的混合酸酐，将上述混合酸酐反应液通过过滤器用氮气压滤至装有4.2KG纯化水，1.4KG牛磺酸，0.4KG氢氧化钠的50升反应釜中，充分搅拌反应3小时，进一步制得牛磺熊去氧胆酸粗品4.0KG。
2)牛磺熊去氧胆酸粗品的精制，按以下步骤进行：
(1)将4.0KG牛磺熊去氧胆酸投入50L反应釜中，加入4KG水和580ml丙酮，，加热搅拌至全部溶解；
(2)搅拌下冷却至-5-0℃，析晶30小时；
(3)放料至过滤器中抽滤，抽干后用冰水(-3-0℃)淋洗滤饼，再次抽干，得牛磺熊去氧胆酸3.3KG(纯度99.6％，HPLC)，其中牛磺鹅去氧胆酸的含量为0.3％，其他最大单杂含量0.05％(液相色谱测定)。
Tauroursodeoxycholic acid (TUDCA)是乌索脱氧胆酸的牛磺酸共轭产物，在多种神经退行性疾病，如阿尔茨海默病、帕金森疾病和亨廷顿疾病中，可作为线粒体稳定剂和抗凋亡试剂。
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ERK
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Caspase-3
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Caspase-12
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Human Endogenous Metabolite
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Tauroursodeoxycholate (TUDCA) suppresses both viability and migration of vascular smooth muscle cells (VSMCs) through inhibition of ERK phosphorylation, by induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) via PKCα. Tauroursodeoxycholate inhibits both the proliferation and migration of VSMCs via inhibition of ERK, through Ca
2+
-dependent PKCα translocation. Tauroursodeoxycholate prevents platelet-derived growth factor (PDGF) and vascular injury-induced MMP-9 expression. The knock-down of MKP-1 using specific si-RNA restores the reduced VSMC viability by Tauroursodeoxycholate (200 μM), which suggests that anti-proliferative effect of Tauroursodeoxycholate depended on the MKP-1 expression.
The effects of Tauroursodeoxycholate (TUDCA) on proliferation and apoptosis of VSMCs in vivo are examined using immunohistochemistry for proliferating cell nuclear antigen (PCNA) and the transferase dUTP nick-end labelling (TUNEL) assay. Tauroursodeoxycholate (10, 50, and 100 mg/kg) increases the caspase 3 activity of injured tissues in a dose-dependent manner, indicating that Tauroursodeoxycholate induces apoptosis of VSMCs in the neointima. Using the injured tissues, further examination and comparison of the phosphorylation level of ERK and MMP-9 expression is performed at 1 week after injury, compared with normal controls. Balloon injury increased both the phosphorylation of ERK and expression of MMP-9 in the tissues. Tauroursodeoxycholate (10, 50, and 100 mg/kg) inhibits phosphorylation of ERK and MMP-9 expression in a dose-dependent manner. Tauroursodeoxycholate (TUDCA) is a hydrophilic bile acid. Tauroursodeoxycholate as a cytoprotective agent improves liver function and can prevent hepatocellular carcinoma by reducing ER stress and apoptosis. Tauroursodeoxycholate significantly reduces expression of apoptosis molecules, such as caspase-3, caspase-12, C/EBP homologous protein, c-Jun N-terminal kinase (JNK), activating transcription factor 4 (ATF4), X-box binding protein (XBP), and eukaryotic initiation factor 2α (eIF2α) in Ang II induced ApoE
-/-
mice (p<0.05). Tauroursodeoxycholate reduces Angiotensin (Ang) II induced abdominal aortic aneurysm (AAA) formation in ApoE
-/-
mice. Tauroursodeoxycholate is used at a dose of 0.5 g/kg/day in treating Ang II induced ApoE
-/-
mice (ER stress inhibitor group). Systolic blood pressure (141.3±5.6 mmHg vs 145.9±8.9 mmHg; p>0.05) and total cholesterol levels (663.6±88.7 mg/dL vs 655.7±65.4 mg/dL; p>0 .05) do not differ between the AAA model group and Tauroursodeoxycholate group. In addition, maximum aortic diameter is significantly smaller in those in Tauroursodeoxycholate group compared with those in the AAA model group (0.95±0.03 mm vs 1.79±0.04 mm; p<0.05). AAA lesion areas are also smaller in those in Tauroursodeoxycholate group than in those in the AAA model group (0.37±0.03 mm
2
vs 1.51±0.06 mm
2
; p<0.05).
用途
生化研究；脂酶加速剂；阴离子去除剂，用于蛋白质的溶解；制备细菌培养基(肠道细菌培养与分离)
用途
用于含量测定/鉴定/药理实验等。
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