Bile acids chemical reactions

Naturally occurring micellar systems, such as phospholipids and bile salts (e.g. cholic and desoxycholic acids, as well as surfactants affect the rates of numerous chemical reactions in vivo and in vitro (Hanahan, 1960 Kavanau, 1965 Knaak et al., 1966a, b Elworthy et al., 1968 Marriott, 1969). The effects of micellization on enzymatic reactions and other biochemical processes have been discussed by Elworthy et al. (1968), Jencks (1969), and Mysels (1969). 

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). 

Prompted by ready-to-hand observations of violent reactions occurring when mineral acids combined with alkaline substances, Sylvius began to think that not only chemical processes could be explained by acid/alkali reactions, but that also diseases themselves resulted from the acidic and alkaline natures of specific bodily fluids (for example, lymph, saliva, pancreatic juice, and bile). The turbulence and strife between acids and alkalis in the body was detectable, he argued, by the presence of effervescence. Because diseases were caused by an overabundance of acidity and alkalinity. 

Cholesterol is primarily restricted to eukaryotic cells where it plays a number of roles. Undoubtedly, the most primitive function is as a structural component of membranes. Its metabolism to bile acids and the steroid hormones is relatively recent in the evolutionary sense. In this chapter, the pathway of cholesterol biosynthesis will be divided into segments which correspond to the chemical and biochemical divisions of this biosynthetic route. The initial part of the pathway is the 3-step conversion of acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The next is the reduction of this molecule to mevalonate, considered to be the rate-controlling step in the biosynthesis of polyisoprenoids. From thence, a series of phosphorylation reactions both activate and decarboxylate mevalonate to isopen tenyl pyrophosphate, the true isoprenoid precursor. After a rearrangement to the allylic pyrophosphate, dimethylallyl pyrophosphate, a sequence of l -4 con-... 

The natural distribution and the chemical structure of bile alcohols and primitive bile acids indicate that these compounds found in lower vertebrates are evolutionary precursors of the common bile acids found in mammalian species. Haslewood proposed that the mechanism of conversion of cholesterol to the common bile acids in mammals is a recapitulation of the evolution of bile salts and thus would entail the intermediary formation of bile alcohols and primitive bile adds similar to or the same as those found in lower species [120]. Thus, studies have been carried out to test whether the naturally occurring bile alcohols and primitive bile acids are intermediates in the biosynthetic pathway between cholesterol and the C24 bile acids in mammals. There is no doubt that such studies contributed to the elucidation of the sequence of reactions in the biosynthesis of the mammalian C24 bile acids. 

The relative content of the dietary fat components varies with different sources but generally the physico-chemical properties are rather similar. For absorption to take place the physico-chemical properties of the fat have to be changed. This takes place as a consequence of the lipolytic activity in the intestinal tract and the addition of bile to chyme. Through lipolytic enzymes the dietary lipids are converted to more polar products. Bile contributes bile salt-phospholipid-cholesterol aggregates to the intestinal content (cf. Chapter 13). The concerted action of these agents is the formation of lipid products in a physical state which allows them to be transported into the enterocyte membrane and onwards for further metabolism in the cell. Bile salts are involved in the proper function of some of these enzymatic reactions and in the formation of product phases on which a normal uptake process is based. Little is known at present of the importance of bile salts for the intracellular reactions following uptake of fat into the enterocyte. Different aspects of intestinal lipid absorption have been reviewed in recent years by Patton [7], Thomson and Dietschy [8], Carey [9], Carey et al. [10], Wells and Direnzo [11], and Grundy [12]. The role of bile acids in fat absorption has been discussed by Holt [13]. 

FIGURE 18-6 Chemical structures of major sterols and cholesterol derivatives. The major sterols in animals (cholesterol), fungi (ergosterol), and plants (stigmasterol) differ slightly in structure, but all serve as key components of cellular membranes. Cholesterol is stored as cholesteryl esters in which a fatty acyl chain (R = hydrocarbon portion of fatty acid) is esterified to the hydroxyl group. Excess cholesterol is converted by liver cells into bile acids (e.g., deoxycholic acid), which are secreted into the bile. Specialized endocrine cells synthesize steroid hormones (e.g., testosterone) from cholesterol, and photochemical and enzymatic reactions in the skin and kidneys produce vitamin D. 

The four isomeric acids can be derived by a series of chemical reactions from cholic acid, which is commercially available (Sigma Chemical). Some of the reactions have already been discussed with regard to structures. This section is intended to provide practical methods by which the four acids can be prepared. Some of the intermediates are by themselves interesting derivatives with regard to the stereochemistry of bile acids. The procedures described here are taken from published works with certain modifications and have been tested in the author s laboratory. 

The purpose of this chapter is to cover the physicochemical properties of cholanic acids and their salts. Some 150 cholanic acids are mentioned in Elsevier s Encyclopedia of Organic Chemistry (27) and about 440 monocar-boxylic, unsubstituted hydroxyl, and carbonyl-substituted bile acids are cataloged by Sobotka (28). Obviously, it would be impossible to deal specifically with each one. Many of these acids are by-products of chemical reactions and are not naturally occurring compounds. Further, meaningful physicochemical data are not available for the great majority of bile acids. 

In the case of a free or glycine-conjugated bile salt, the initial solution contains the soluble sodium salt of the bile acid which is fully ionized at high pH (10.5). Titration with HCl is carried out until all the bile acid anion is in the form of an insoluble acid. The chemical reaction in simplified form is... 

Fontana also published on formic acid and vegetable acids, potash and soda, the analysis of malachite, inflammable air, and bile. His measurements on the densities of gases were important but his most outstanding work was a series of experiments on respiration, the calcination of metals, adsorption of gases by charcoal (see p. 296), the production of inflammable gas from water and heated charcoal, etc., in which, e.g., he showed that the weight remains constant in chemical reactions, and that different gases follow Boyle s law. ... 

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