胆酸 | 81-25-4

• 物质功能分类: 原料药 - 消化系统用药 - 利胆药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 胆酸
• 中文别名: 胆汁酸；3Alpha.7Alpha.12Alpha-三羟胆烷酸；3alpha,7alpha,12alpha-三羟基-5beta-胆烷酸；胆甾烷酸；胆酸,由牛或羊胆汁中提取；3α,7α,12α-三羟基-5β-胆烷酸
• 英文名称: cholate
• 英文别名: cholic acid；3α,7α,12α-trihydroxy-5β-cholan-24-oic acid；(4R)-4-[(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
• CAS: 81-25-4
• 化学式: C₂₄H₄₀O₅
• mdl: MFCD02940838
• 分子量: 408.579
• InChiKey: BHQCQFFYRZLCQQ-OELDTZBJSA-N

物化性质

• 熔点：
  200-201 °C (lit.)
• 比旋光度：
  36 º (c=0.6, 95% EtOH)
• 沸点：
  449.08°C (rough estimate)
• 密度：
  1.0310 (rough estimate)
• 闪点：
  9℃
• 溶解度：
  溶于甲醇，溶解度为0.1g/mL，澄清
• LogP：
  2.03-2.615 at 20℃
• 物理描述：
  Solid; [HSDB] White powder; [MSDSonline]
• 颜色/状态：
  Plates from dilute acetic acid
• 味道：
  Bitter with sweetish aftertaste
• 蒸汽压力：
  9.66X10-15 mm Hg at 25 °C (est)
• 水溶性：
  -3.37
• 亨利常数：
  Henry's Law constant = 5.16X10-13 atm-cu m/mol at 25 °C (est)
• 稳定性/保质期：

  Stable under recommended storage conditions.

• 旋光度：
  Specific optical rotation: +37 deg at 20 °C/D (c = 0.6 in alcohol)
• 分解：
  When heated to decomposition it emits acrid smoke and irritating fumes.
• 解离常数：
  4.98 (at 20 °C)
• 碰撞截面：
  197.3 Ų [M+Na]+ [CCS Type: DT, Method: single field calibrated with Agilent tune mix (Agilent)]

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  98
• 氢给体数：
  4
• 氢受体数：
  5

ADMET

代谢

胆固醇侧链羟基化在胆酸合成中的作用机制和顺序在隔离灌注的兔肝中进行了研究。比较了26-羟基化和25-羟基化在兔胆酸生物合成中的重要性。当肝脏被灌注5beta-[G-(3)H]胆甾烷-3alpha, 7alpha-二醇、5beta-[G-(3)H]胆甾烷-3alpha, 7alpha, 12alpha-三醇和5beta-[G-(3)H]胆甾烷-3alpha, 7alpha, 26-三醇时，观察到[G-(3)H]胆酸的形成。胆汁中没有检测到[G-(3)H]鹅脱氧胆酸。这些发现表明，鹅脱氧胆酸的潜在前体在12alpha位置的羟基化是在胆固醇侧链羟基化之前或之后进行的。此外，当这些化合物在肝脏中灌注时，胆汁中没有发现其他中间体（四羟基或五羟基胆醇）。当兔肝被灌注5beta-[24-(14)C]胆甾烷-3alpha, 7alpha, 25-三醇时，在胆汁中检测到了胆酸前体。5beta-[24-(14)C]胆甾烷-3alpha, 7alpha, 25-三醇在肝脏的12alpha位置被羟基化，产生相应的5beta-胆甾烷-3alpha, 7alpha, 12alpha, 25-四醇。四醇进一步代谢为一组五醇（5beta-胆甾烷-3alpha, 7alpha, 12alpha, 22, 25-五醇；5beta-胆甾烷-3alpha, 7alpha, 12alpha, 23, 25-五醇；5beta-胆甾烷-3alpha, 7alpha, 12alpha, 24, 25-五醇和5beta-胆甾烷-3alpha, 7alpha, 12alpha, 25, 26-五醇）。从5beta-胆甾烷-3alpha, 7alpha, 25-三醇灌注得到的主要胆酸是胆酸。实验表明，在兔肝中，12alpha-羟基化可以在胆固醇侧链在C-25（5beta-胆甾烷-3alpha, 7alpha, 25-三醇）或C-26（5beta-胆甾烷-3alpha, 7alpha-26-三醇）羟基化之后发生。显然，兔可以通过经典的26-羟基化途径以及通过25-羟基化中间体形成胆酸。

The mechanism and sequence of side chain hydroxylation of cholesterol in bile acid synthesis was studied in the isolated perfused rabbit liver. A comparison was made between the importance of 26- and 25-hydroxylation in cholic acid biosynthesis in the rabbit. The formation of [G-(3)H]cholic acid was observed when the liver was perfused with 5beta-[G-(3)H]cholestane-3alpha, 7alpha-diol, 5beta-[G-(3)H]cholestane-3alpha, 7alpha-12alpha-triol, and 5beta-[G-(3)H]cholestane-3alpha, 7alpha, 26-triol. No [G-(3)H]chenodeoxycholic acid was detected in the bile. These findings indicate that potential precursors of chenodeoxycholic acid were hydroxylated at position 12alpha either subsequent to or before hydroxylation of the cholesterol side chain. In addition, no other intermediates (tetrahydroxy or pentahydroxy bile alcohols) were found in the bile when these compounds were perfused in the liver. Bile acid precursors were detected in bile when the rabbit liver was perfused with 5beta-[24-(14)C]cholestane-3alpha, 7alpha, 25-triol. The 5beta-[24-(14)C]cholestane-3alpha, 7alpha, 25-triol was hydroxylated in the liver at the 12alpha position to yield the corresponding 5beta-cholestane-3alpha, 7alpha, 12alpha, 25-tetrol. The tetrol was further metabolized to a series of pentols (5beta-cholestane-3alpha, 7alpha, 12alpha, 22, 25-pentol; 5beta-cholestane-3alpha, 7alpha, 12alpha, 23, 25-pentol; 5beta-cholestane-3alpha, 7alpha, 12alpha, 24, 25-pentol; and 5beta-cholestane-3alpha, 7alpha, 12alpha, 25, 26-pentol). The major bile acid obtained from the perfusion of the 5beta-cholestane-3alpha, 7alpha, 25-triol was cholic acid. The experiments indicated that in the rabbit liver 12alpha-hydroxylation can occur after hydroxylation of the cholesterol side chain at either C-25 (5 beta-cholestane-3alpha, 7alpha, 25-triol) or C-26 (5beta-cholestane-3alpha, 7alpha-26-triol). Apparently, the rabbit can form cholic acid via the classical 26-hydroxylation pathway as well as via 25-hydroxylated intermediates.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在经典的胆酸生物合成中，胆固醇的一系列环修饰发生在侧链裂解之前，并产生5beta-胆烷-3alpha, 7alpha, 12alpha-三醇。然后，三醇的侧链反应通过线粒体的27-羟基化途径或微囊体的25-羟基化途径进行。我们已经开发出特异和精确的测定方法来测量这两个途径中关键酶的活性，即5beta-胆烷-3alpha, 7alpha, 12alpha-三醇25-和27-羟化酶以及5beta-胆烷-3alpha, 7alpha, 12alpha, 25-四醇23R-, 24R-, 24S-和27-羟化酶。通过一次性硅胶柱的纯化，将线粒体或微囊体孵化混合物的提取物转化为三甲基硅醚，并通过高分辨率模式的气相色谱-质谱法进行定量分析。与在丙酮中添加底物相比，使用2-羟基丙基-beta-环糊精的人类肝脏中，线粒体三醇27-羟化酶活性增加了132%，但微囊体25-羟基化途径（三醇25-羟化酶和5beta-胆烷-3alpha, 7alpha, 12alpha, 25-四醇23R-, 24R-, 24S-和27-羟化酶）的酶活性降低了13%-60%。与人类肝脏相比，小鼠和兔子的两个途径中的酶活性通常是2到4倍。在所有物种中，微囊体三醇25-羟化酶活性是线粒体三醇27-羟化酶活性的4到11倍，但在我们的实验条件下，四醇24S-羟化酶的活性与三醇27-羟化酶的活性相似。在兔子肝脏中，当胆酸合成受到干扰后，研究了两个途径的调节。胆固醇饲养上调了参与25-（64%-142%）和27-（77%）羟基化途径的酶活性，而胆汁引流仅上调了25-羟基化途径（178%-371%）中的酶。使用这些新的测定方法，我们证明了胆酸生物合成中的25-和27-羟基化途径在小鼠和兔子肝脏中比人类肝脏更活跃，并且在兔子肝脏中是分别调节的。

In classic cholic acid biosynthesis, a series of ring modifications of cholesterol precede side chain cleavage and yield 5beta-cholestane-3alpha, 7alpha, 12alpha-triol. Side chain reactions of the triol then proceed either by the mitochondrial 27-hydroxylation pathway or by the microsomal 25-hydroxylation pathway. We have developed specific and precise assay methods to measure the activities of key enzymes in both pathways, 5beta-cholestane-3alpha, 7alpha, 12alpha-triol 25- and 27-hydroxylases and 5beta-cholestane-3alpha, 7alpha, 12alpha, 25-tetrol 23R-, 24R-, 24S- and 27-hydroxylases. The extracts from either the mitochondrial or microsomal incubation mixtures were purified by means of a disposable silica cartridge column, derivatized into trimethylsilyl ethers, and quantified by gas chromatography;-mass spectrometry with selected-ion monitoring in a high resolution mode. Compared with the addition of substrates in acetone, those in 2-hydroxypropyl-beta-cyclodextrin increased mitochondrial triol 27-hydroxylase activity 132% but decreased activities of the enzymes in microsomal 25-hydroxylation pathway (triol 25-hydroxylase and 5beta-cholestane-3alpha, 7alpha, 12alpha, 25-tetrol 23R-, 24R-, 24S- and 27-hydroxylases) 13;-60% in human liver. The enzyme activities in both pathways were generally 2- to 4-times higher in mouse and rabbit livers compared with human liver. In all species, microsomal triol 25-hydroxylase activities were 4- to 11-times larger than mitochondrial triol 27-hydroxylase activities but the activities of tetrol 24S-hydroxylase were similar to triol 27-hydroxylase activities in our assay conditions. The regulation of both pathways in rabbit liver was studied after bile acid synthesis was perturbed. Cholesterol feeding up-regulated enzyme activities involved in both 25- (64;-142%) and 27- (77%) hydroxylation pathways, while bile drainage up-regulated only the enzymes in the 25-hydroxylation pathway (178;-371%). Using these new assays, we demonstrated that the 25- and 27-hydroxylation pathways for cholic acid biosynthesis are more active in mouse and rabbit than human livers and are separately regulated in rabbit liver.

来源:Hazardous Substances Data Bank (HSDB)

代谢

脱氧胆酸是胆酸的主要代谢产物。患有3alpha-羟基类固醇脱氢酶（3alpha-HSD）缺乏症和delta4-3-氧代胆固醇缺乏症的病人以及胆酸代谢正常的受试者，在接受胆酸治疗后，血清和胆汁中主要含有胆酸和脱氧胆酸，而鹅脱氧胆酸及其代谢物似乎有所减少。因此，在胆酸治疗下，患者会暴露于比正常更高的脱氧胆酸浓度，尽管这些浓度的确切量化尚未被描述。在单次和重复剂量研究中，脱氧胆酸在大约一半的剂量下就显示出致死效应、胃肠道和肝脏毒性，而胆酸需要更高的剂量才能产生相同的效果。因此，认为脱氧胆酸比胆酸更有毒性，实际上可能是胆酸毒性的原因之一。脱氧胆酸的细菌致突变性数据存在争议，但在体外微核试验中脱氧胆酸显示出基因毒性。此外，通过彗星试验研究了胆酸（主要集中在鹅脱氧胆酸和脱氧胆酸）对人类结肠细胞和结肠肿瘤细胞HT 29的基因毒性潜力。在两种细胞类型中，观察到两种胆酸引起的明显的剂量依赖性基因毒性效应，其中脱氧胆酸更具基因毒性。细胞的存活率似乎大于75%。使用经过Ⅲ型核酸酶修饰的彗星试验表明，DNA损伤可能是由活性氧种类的产生介导的，但通过加入抗氧化剂得到了一定程度的保护。短期致癌性研究建议，脱氧胆酸像胆酸一样具有促进致癌性的特性。在大鼠肝脏中，脱氧胆酸（75-150 mg/kg）显示出促进作用，与对照组相比，接受致癌物二乙基亚硝胺（DEN）单独处理的相应对照组，alpha-谷氨酰转肽酶阳性（alpha-GT+）肝焦点显著增加。脱氧胆酸（20 mg/kg）在大鼠结肠中增强了氧化偶氮甲烷（AOM）诱导的异常隐窝焦点的发育和生长。在平行研究中，在没有AOM的情况下，脱氧胆酸并没有显著诱导异常隐窝焦点。然而，一项研究得出结论，脱氧胆酸可能不仅作为促进剂，还可能是多阶段致癌过程启动剂的结论。

Deoxycholic acid is the main metabolite of cholic acid. Patients with 3alpha-HSD deficiency and delta4-3-oxoR deficiency and subjects with a normal bile acid metabolism have shown that upon treatment with cholic acid, serum and bile predominantly contain cholic acid and deoxycholic acid, while chenodeoxycholic acid and its metabolites appear to be reduced. Under cholic acid treatment, patients are therefore exposed to higher than normal deoxycholic acid concentrations, although the exact quantifications of these concentrations have not been described. In single- and repeat-dose studies, deoxycholic acid showed lethal effects, gastrointestinal and hepatic toxicities at approximately half the doses needed for cholic acid to produce the same effects. It is therefore considered that deoxycholic acid is more toxic than cholic acid and may in fact be the causative agent of some of cholic acid's toxicity. Mutagenicity data from bacterial test for deoxycholic acid is ambiguous but deoxycholic acid was genotoxic in an in vitro micronucleus assay. Additionally, ... the genotoxic potential of BA (focusing on chenodeoxycholic acid and deoxycholic acid) on human colonocytes and colon tumor cells HT 29 by a comet assay /was investigated/. In both cell types a clear dose-dependent genotoxic effect induced by the two bile acids was observed, with deoxycholic acid being more genotoxic. Viability of cells appeared to be greater than 75%. Use of a nuclease III modified comet assay suggested that the DNA damage could be mediated by reactive oxygen species production but was somewhat protected by inclusion of anti-oxidants. Short term carcinogenicity studies suggest that deoxycholic acid like cholic acid has carcinogenicity promoting properties. In rat liver, deoxycholic acid (75-150 mg/kg) exerted promoting activity as evidenced by significantly increased values of alpha-glutamyl transpeptidase-positive (alpha-GT+) liver foci compared with the corresponding controls given the carcinogen, diethylnitrosamine (DEN) alone. Deoxycholic acid (20 mg/kg) enhanced the development and growth of azoxymethane (AOM)-induced aberrant crypt foci in rat colons. In a parallel study, deoxycholic acid in the absence of AOM did not significantly induce aberrant crypt foci. However, /a study/ concluded that deoxycholic acid may act not only as promoters but also initiators of the multistage process of carcinogenesis.

来源:Hazardous Substances Data Bank (HSDB)

代谢

胆酸已知的代谢产物包括胆酸葡萄糖苷酸。

Cholic acid has known human metabolites that include Cholic acid glucuronide.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

识别和使用：胆酸用于生物化学研究，作为药物中间体，以及作为食品中的乳化剂（最高0.1%）。它也是一种药物，用于治疗由于单个酶缺陷引起的胆酸合成障碍，以及作为辅助治疗过氧化物酶体障碍，包括在表现出肝脏疾病、脂肪泻或因脂肪溶性维生素吸收减少引起的并发症的泽尔韦格谱系障碍患者。人类暴露和毒性：胆酸是一种主要胆酸。主要胆酸在肝脏中生物合成，是正常胆汁的关键成分。当作为治疗胆酸合成障碍患者的药物配方和使用时，主要的毒性效应是对肝功能的影响。给患者输注的胆酸剂量旨在恢复相当于人体内生理存在的浓度。因此，患者对胆酸和脱氧胆酸的任何感知到的基因毒性风险将与正常健康成人内源性地产生这些胆酸的风险相当。总的来说，胆酸在体外进行的基因毒性测试中显示了非显著的诱变活性。动物研究：胆酸已知通过肝脏的的法尼醇X受体（FXR-SHP）和肠道（FXR-Fgf15）来调节胆酸合成和运输。缺乏维持肝胆酸水平的法尼醇X受体（FXR）的小鼠对胆酸诱导的肝毒性非常敏感。在喂食0.25%胆酸饮食五天后，血清天门冬氨酸转氨酶（AST）活性升高了15.7倍，而在喂食0.25和1%胆酸饮食的野生型小鼠中，血清AST仅略有增加（分别为1.7倍和2.5倍）。在大鼠化学诱导结肠癌模型中，研究了主要胆酸作为可能的结肠肿瘤促进剂或抑制剂。胆酸喂食增加了带有肿瘤的动物数量、每只动物的肿瘤数量以及带有肿瘤的动物的平均肿瘤数量。肿瘤增强归因于胆酸的细菌代谢物脱氧胆酸。给雄性大鼠连续三天喂食胆酸（饮食的1.0%）导致结肠隐窝柱中的DNA合成上皮细胞数量增加，与对照组或0.2%胆酸喂食的大鼠相比。通过使用Salmonella typhimurium TA100和TA98作为测试菌株的波动试验检测了胆酸的诱变性。胆酸和脱氧胆酸在这种测试中具有诱变性。胆酸的诱变性大约是中等强诱变剂甲基甲磺酸的四分之一。怀孕的仓鼠摄入0.5%胆酸，会导致成年动物不同程度的导管/小导管增殖和肝胆炎症损伤，幼年动物损伤程度较轻；并且幼仔的数量也会减少。在怀孕期间，仓鼠摄入这些胆酸会对母体和新生儿的肝胆系统造成不同程度的毒性。在大鼠发育研究中，胆酸处理组的大鼠胎儿大脑出现了明显的病理变化，神经元退化和线粒体肿胀主要出现在低胆酸组，而神经元坏死和线粒体减少主要出现在高胆酸组。

IDENTIFICATION AND USE: Cholic acid is used in biochemical research, as a pharmaceutical intermediate, and as an emulsifying agent in foods (up to 0.1%). It is also a medication used for the treatment of bile acid synthesis disorders due to single enzyme defects and for the adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications