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.
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.
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.
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 from decreased fat soluble vitamin absorption. HUMAN EXPOSURE AND TOXICITY: Cholic acid is a primary bile acid. Primary bile acids are biosynthesized in the liver and are key constituents of normal bile. When formulated and used as a treatment for patients with bile acid synthesis disorders the major toxic effect is on liver function. The dose of cholic acid to be administered to the patients is intended to restore a concentration that is equivalent to that physiologically present in humans. Therefore any perceived genotoxic risk from cholic acid and deoxycholic acid to the patients would be equivalent to that of a normal healthy adult that produces these bile acids intrinsically. Overall, cholic acid showed nonsignificant mutagenic activity in a battery of genotoxicity tests performed in vitro. ANIMAL STUDIES: Bile acids are known to regulate bile acid synthesis and transport by the farnesoid X receptor in the liver (FXR-SHP) and intestine (FXR-Fgf15). Mice lacking the farnesoid X receptor (FXR) involved in the maintenance of hepatic bile acid levels are highly sensitive to cholic acid-induced liver toxicity. Serum aspartate aminotransferase (AST) activity was elevated 15.7-fold after feeding a 0.25% cholic acid diet for five days, whereas only slight increases in serum AST (1.7- and 2.5-fold) were observed in wild-type mice fed 0.25 and 1% cholic acid diet, respectively. Primary bile acids were studied as possible colon tumor promoters or inhibitors in a rat model of chemically induced colon cancer. Cholic acid feeding increased the number of animals with tumors, the number of tumors per animal, and the number of tumors per tumor-bearing animal. Tumor enhancement was attributed to deoxycholic acid, the bacterial metabolite of cholic acid. Administration of cholic acid (1.0% of the diet) to male rats for 3 days resulted in increased numbers of DNA synthesizing epithelial cells per colonic crypt column as compared to those found in either control or 0.2% cholic acid-fed rats. The mutagenicity of bile acids was detected by a fluctuation test using Salmonella typhimurium TA100 and TA98 as tester strains. Cholic acid and deoxycholic acid were mutagenic in this test. The mutagenicity of the bile acids on a molar basis was roughly one-fourth that of methyl methanesulfonate, a moderately potent mutagen. 0.5% cholic acid ingested by pregnant hamsters, caused ductal/ductular proliferation and hepatobiliary inflammatory damage in a different degree of intensity in adult animals and mild intensity in the young; and also the number of the young was reduced in the litter. The ingestion of these bile acids by hamsters, during gestational period caused different degrees of toxicity on maternal and neonatal hepatobiliary systems. In rat developmental studies there was apparent pathological change of fetal rats brain in cholic acid-treated groups, the neuronal degeneration and the mitochondria swelling was mainly found in low cholic acid group, the neuronal necrosis and the mitochondria decrease was mainly found in high cholic acid group.
In small, open label trials, cholic acid was found to improve fat soluble vitamin absorption and to ameliorate many of the clinical features of the bile acid synthetic defects including improvement in serum aminotransferase levels, decrease in bilirubin and jaundice and improvement in general health and growth. In some instances, higher doses of cholic acid were associated with elevations in serum aminotransferase levels. These abnormalities, however, were mild, transient and rapidly reversed with lowering the daily dose. There have been no reports of clinically apparent liver injury with jaundice attributed to cholic acid therapy given in standard doses.
来源:LiverTox
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
健康影响
慢性高水平的胆酸与家族性高胆酸血症有关。
Chronically high levels of cholic acid are associated with Familial Hypercholanemia.
Aluminum-based antacids have been shown to adsorb bile acids in vitro and can reduce the bioavailability of Cholbam. Take Cholbam at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after an aluminum-based antacid.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
服用后，胆酸首先会被小肠吸收，然后通过血液运输到肝脏进行进一步处理。
Following ingestion, absorption of cholic acid will first be by the small intestine, and is then transported to the liver by the blood for further processing.
Orally administered cholic acid is subject to the same metabolic pathway as endogenous cholic acid. Cholic acid is absorbed by passive diffusion along the length of the gastrointestinal tract. Once absorbed, cholic acid enters into the body's bile acid pool and undergoes enterohepatic circulation mainly in conjugated forms. In the liver, cholic acid is conjugated with glycine or taurine by bile acid-CoA synthetase and bile acid-CoA: amino acid N-acetyltransferase. Conjugated cholic acid is actively secreted into bile mainly by the Bile Salt Efflux Pump (BSEP), and then released into the small intestine, along with other components of bile. Conjugated cholic acid is mostly re-absorbed in the ileum mainly by the apical-sodium-dependent-bile acid transporter, passed back to the liver by transporters including sodium-taurocholate cotransporting polypeptide and organic anion transport protein and enters another cycle of enterohepatic circulation. Any conjugated cholic acid not absorbed in the ileum passes into the colon where deconjugation and 7-dehydroxylation are mediated by bacteria to form cholic acid and deoxycholic acid which may be re-absorbed in the colon or excreted in the feces. The loss of cholic acid is compensated by de-novo synthesis of cholic acids from cholesterol to maintain the bile acid pool in healthy subjects.
Excretion studies in rat showed that cholic acid (CA) is almost exclusively excreted in the feces in the form of metabolite. Only minor amounts of CA were found in the unconjugated form in rat feces. Urinary excretion of bile acids is minimal and in mice fed a 1% CA diet, the excretion of bile acids was 2000-fold higher in feces than in urine
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
胆酸在大鼠的小肠中主要在远端（回肠）而不是近端段被吸收。
Cholic acid was shown to be mainly absorbed in the distal (ileal) rather than proximal segments of the small intestine in the guinea pig.
Small molecules for treatment of hypercholesterolemia and related diseases
申请人：Sircar C. Jagadish
公开号：US20050277690A1
公开（公告）日：2005-12-15
The present invention provides compositions adapted to enhance reverse cholesterol transport in mammals. The compositions are suitable for oral delivery and useful in the treatment and/or prevention of hypercholesterolemia, atherosclerosis and associated cardiovascular diseases.
[EN] CATHEPSIN INHIBITORS<br/>[FR] INHIBITEURS DE LA CATHEPSINE
申请人：ACADEMISCH ZIEKENHUIS LEIDEN
公开号：WO2019112426A1
公开（公告）日：2019-06-13
This invention relates to compounds that are useful as inhibitors, in particular as inhibitors of Cathepsin K (CatK), and to a method of inhibiting cathepsin activity, comprising administering a compound or formulation comprising a compound according to the invention.
A Bifunctional Copper Catalyst Enables Ester Reduction with H<sub>2</sub>: Expanding the Reactivity Space of Nucleophilic Copper Hydrides
作者：Birte M. Zimmermann、Trung Tran Ngoc、Dimitrios-Ioannis Tzaras、Trinadh Kaicharla、Johannes F. Teichert
DOI：10.1021/jacs.1c09626
日期：2021.10.13
activation of esters through hydrogen bonding and formation of nucleophilic copper(I) hydrides from H2, resulting in a catalytic hydride transfer to esters. The reduction step is further facilitated by a proton shuttle mediated by the guanidinium subunit. This bifunctional approach to ester reductions for the first time shifts the reactivity of generally considered “soft” copper(I) hydrides to previously
采用基于铜 (I)/NHC 配合物和胍有机催化剂的双功能催化剂，促进了以 H 2作为末端还原剂的催化酯还原成醇。这里采用的方法能够通过氢键同时活化酯，并从 H 2形成亲核的氢化铜 (I) ，从而导致氢化物催化转移到酯。由胍亚基介导的质子穿梭进一步促进了还原步骤。这种酯还原的双功能方法首次将通常认为的“软”氢化铜 (I) 的反应性转变为以前不反应的“硬”酯亲电子试剂，并为用催化剂和 H 2替代化学计量还原剂铺平了道路.
Pharmaceutical compositions of drug-oligomer conjugates and methods of treating diseases therewith
申请人：——
公开号：US20030069170A1
公开（公告）日：2003-04-10
Pharmaceutical compositions that include a drug-oligomer conjugate, a fatty acid component, and a bile salt component are described. The drug is covalently coupled to an oligomeric moiety. The fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1:5 and 5:1. Methods of treating diseases in a subject in need of such treatment using such pharmaceutical compositions are also provided, as are methods of providing such pharmaceutical compositions.
Esterification of Aryl/Alkyl Acids Catalysed by N-bromosuccinimide under Mild Reaction Conditions
作者：Klara Čebular、Bojan Božić、Stojan Stavber
DOI：10.3390/molecules23092235
日期：——
(NBS) has been promoted as the most efficient and selective catalyst among the NXSs in the reaction of direct esterification of aryl and alkyl carboxylic acids. Comprehensive esterification of substituted benzoic acids, mono-, di- and tri-carboxy alkyl derivatives has been performed under neat reactionconditions. The method is metal-free, air- and moisture-tolerant, allowing for a simple synthetic and
