Bile acids derivative formation

Table 3 Formation of the inclusion compounds of bile acid derivatives with their host-guest ratios. 

G. Drugs That Inhibit the Formation of Gallstones The formation of cholesterol gallstones can be inhibited by several drugs, though none are dramatically effective. Such drugs include the bile acid derivatives chenodiol and ursodiol. Chenodiol appears to reduce the secretion of bile acids by the liver, while the mechanism of action of ursodiol is unknown. 

Formyl derivatives are also popular in situations where several groups have to be blocked, as in steroid analysis, because the formyl group adds little to the molecular weight. To prevent the formation of artifacts, the strength of the formic acid should be kept at 95% and reaction allowed to take place for 30 min at 40°C. Alternatively, sodium formate can be used, an example of which is in the preparation of the enol rert-butyldi-methylsilyl derivatives of steroids and bile acids. Sodium formate solution (1 mg in 100 p,l) is dried under a stream of nitrogen in a 1 ml reaction tube fitted with a Teflon-lined screw cap. The tube is then heated to 270°C for 30 min, cooled, and 10 p,g of the steroid in 100 p,l of methanol added. The solvent is evaporated under a stream... 

The choice of bile acid derivative depends on the nature and complexity of the bile acid mixture to be analyzed. Derivative formation is described in the chapter on gas chromatography. Generally it is of advantage to use... 

In a smdy by Shen et al., a series of experiments were conducted on structurally similar bile acid derivatives (BAs) to test the effects of concentration and molar ratio of BAs to M"+ on the gelation properties. It was reported that metal ions like Ca +, Au +, Mg +and Ag+ could trigger the self-assembly of most BAs. It was also observed that irradiation of light facilitates the formation of Au NPs in Ba-Au +. Ba-Ag+ hydrogel systems were found to have a temperature sensitive... 

They developed a continuum elastic-free energy model that suggests these observations can be explained as a first-order mechanical phase transition. In other recent work on steroids, Terech and co-workers reported the formation of nanotubes in single-component solutions of the elementary bile steroid derivative lithocholic acid, at alkaline pH,164 although these tubules do not show any chiral markings indicating helical aggregation. 

We have recently shown, in Seg-1 cells derived from a patient with esophageal adenocarcinoma, that bile acids and low pH induce the dramatic formation of autophagic vacuoles (unpublished data). We also showed that persistent treatment of Het-IA cells (derived from normal human esophageal squamous epithelium) with a bile-acid cocktail and low pH resulted in the development of mutated clones that contain a partly duplicated chromosome 16 (unpublished data from a CGH microarray). In addition to other protective genes, this chromosome 16 duplication resulted in the duplication of the major ATPase necessary for the acidification of vesicles associated with the autophagic process. 

Formation of cholesterol and some of its derivatives. All of the carbon atoms of cholesterol are derived from acetyl-CoA by way of mevalonate in a pathway with 33 reaction steps. From cholesterol a wide variety of steroids and bile acids and bile salts are formed. Many of the reactions leading to cholesterol derivatives are organ-... 

Bile-acid formation in rats involves hydroxylation to give 7a- and 6j8-hydroxy-derivatives. In many cases, no isotope effect was observed on hydroxylation of the appropriate labelled sterol. These examples involve cytochrome P-450 in the oxidation. However, oxidation of [7a- H,24- C]deoxycholic acid or tauro-deoxycholic acid to the corresponding cholic acid showed an isotope effect of 3.8 on examination of recovered starting material. 

Substitution, Elimination, and Solvolysis.—7a-Hydroxycholesterol, an intermediate in the enzymic formation of bile acids from cholesterol, has been difficult to obtain by chemical methods. It is now available from the accessible 7/3-isomer by reaction with HBr at —78°C, which affords 7a-bromocholesteryl benzoate (21), followed by acetolysis (KOAc-HOAc) to form the 7a-acetoxy-derivative (22). 

Although cholesterol is the major source of 5)9-bile acids, an unsaturated acid, 3)8-hydroxy-5-cholenic acid [174] has been found in meconium, mainly as the sulfate [175], in bile of a boy with a deficiency of 3)8-hydroxysteroid dehydrogenase [176], and in urine of healthy persons and individuals with liver disease [164]. The details of metabolism of 3)8-hydroxy-5-cholenic acid to lithocholate have not been entirely elucidated, but the mechanism for conversion of the 3/8-hydroxy-A to the 3-oxo-A derivative has been formulated in the C27 series (cf. Chapter 9). Briefly, the 3)8-ol is dehydrogenated by a microsomal enzyme fortified with NAD to provide the 3-oxo-A system [177,178]. Whether a A - A" isomerase is essential is not known, since there is no direct evidence for the formation of the intermediary 3-oxo-A system the rate-limiting step is the dehydrogenation of the 3)8-ol which may prevent accumulation of the 3-oxo-A system [177]. The reduction of the double bond at 4-5 to the 5)8- or 5a-bile acid is catalyzed by the respective A -3-oxosteroid 5)8- or 5 -reductase obtained from liver cytosol [170], and has been purified about 10-fold [178]. The formation of the 3-oxo-5/9 derivative requires the enzyme and NADPH the proton from the A side (4A-NADPH) appeared in the product as the 5)8-H, whereas the proton at C-4 is derived from the aqueous medium. Formation of the 5a derivative requires (4B-NADPH) in a similar mechanism (Fig. 4) [179], Reduction of the 3-0X0 product is then catalyzed by 3a-hydroxysteroid dehydrogenase as discussed above. 

The export of phospholipids and cholesterol can be simultaneous owing to the activity of various members of the ABC superfamily (see Table 18-2). The best-understood example of this phenomenon is in the formation of bile, an aqueous fluid containing phospholipids, cholesterol, and bile acids, which are derived from cholesterol. After export from liver cells, phospholipids, cholesterol, and bile acids form water-soluble micelles in the bile, which is delivered through ducts to the gallbladder, where it is stored and concentrated. In response to a fat-containing meal, bile is released into the small intestine to help emulsify dietary lipids and thus aid in their digestion and absorption into the body. As we shall see later, the alteration of biliary metabolism by drugs can be used to prevent heart attacks. 

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