Conjugated bile acids formation

In addition, three types of lipophilic conjugates have been found in pyrethroid metabolism studies (Fig. 4). They are cholesterol ester (fenvalerate) [15], glyceride (3-PBacid, a common metabolite of several pyrethroids) [16], and bile acid conjugates (fluvalinate) [17]. It is noteworthy that one isomer out of the four chiral isomers of fenvalerate yields a cholesterol ester conjugate from its acid moiety [15]. This chiral-specific formation of the cholesterol ester has been demonstrated to be mediated by transesterification reactions of carboxylesterase(s) in microsomes, not by any of the three known biosynthetic pathways of endogenous cholesterol esters... 

D. J. Sweeney, S. Barnes, R. B. Diasio, Formation of Conjugates of 2-Fluoro-/3-alanine and Bile Acids during the Metabolism of 5-Fluorouracil and 5-Fluoro-2-deoxyuridine in the Isolated Perfused Liver , Cancer Res. 1988, 48, 2010-2014. 

The bile acids are usually conjugated to the amino acids, glycine or taurine, as shown for the formation of glycocholate in figure 20.21. It is in this form that the bile acids are secreted via the gallbladder into the intestine where they are critically important for the solubilization of dietary lipids. At pH 7, these acids exist as the sodium salts and are often referred to as bile salts. Of course in the acidic environment of the small intestine, they occur largely in their acidic form. 

Additional reactions of glycine include its ability to become conjugated with bile acids to form conjugated bile salts (see Chapter 19), formation of heme (Chapter 7), formation of purine nucleotides (Chapter 10), formation of creatine (see later), and the formation of hippuric acid from benzoic acid. In the last case, an amide linkage is formed between the carboxyl group of benzoic acid and the amino group of glycine. 

In the duodenum s alkaline environment, bile acids become bile salts (e.g. sodium glyco-cholate). Bile acids are conjugated (joined together) with glycine or taurine, via formation of... 

Another type of conjugation occurring with bile acids involves the hydroxyl groups. These may form sulfate esters or conjugates with glucuronic acid, usually at the 3a position. The formation of sul te esters was first demonstrated as a possible bile acid metabolic pathway in man by Palmer and Bolt (P3). These bile acids can be detected as excretion products in the urine (A6). 

The liver, and also bacteria in the small and large intestine, can cause other structural modifications to bile acids as they undergo their entero-hepatic cycle. The formation of sulfate esters, already mentioned with respect to lithocholate in Section 4.2.1, is carried out primarily in the liver in man by a sulfotransferase (Lll). Other bile acids can also be sulfoconjugated to a small extent, mainly at the 3a-hydroxyl position. Bacteria, which have been isolated anaerobically from human feces, are known to possess bile acid sulfatase activity, which removes the 3a-sul te group of chenodeoxycholic and cholic acids (H24). The action of this bacterial enzyme probably explains why only trace amounts of sul ted bile acids, which are poorly absorbed in the intestine, are detected in the feces (12). Another type of bile acid conjugate, which has been identified in the urine of healthy subjects and patients with hepatobiliary disease, is the glucuronide (A7, S41). Both the liver and extrahepatic tissues, such as the kidney and small intestinal mucosa, are capable of glucuronidation of bile acids in man (M14). 

The conversion of cholesterol into bile acids represents the most obvious example of the high capacity of the liver to convert lipid-soluble material into excretable water-soluble products. In principle, the reactions in the formation of bUe acids are very similar to those generally involved in the metabolism and detoxication of various lipids and drugs hydroxylations, oxidations, and conjugations. In contrast to detoxication reactions, however, some of the reactions are highly specific and at least one of the hydroxylations is subject to metabolic control. In view of the importance of the rate of elimination of cholesterol in diseases such as atherosclero-... 

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