Bile Acid Conjugate Synthesis

Ml. Delermi nation of Bile Acid Conjugate Synthesis... 

The terminal step in the biosynthesis of bile acids from cholesterol is represented by the enzymatic synthesis of water-soluble bile acid conjugates of taurine and/or glycine through a peptide bond, as shown in Fig. 1. 

The demonstration by Bergstrom et al. (4,5) in 1953 of the conversion of deoxycholic acid to taurocholic acid in the rat in vivo and by rat liver slices paved the way for studies on 7a-hydroxylation and conjugation of bile acids. The early work on the synthesis of bile acid conjugates in vitro utilized slices or homogenates of rat and human liver, and the enzymatic reaction was followed by the incorporation of radioactivity from carboxyl- C-labeled bile acids into the corresponding taurine and glycine conjugates (6,7). The... 

In Section II, we have discussed the enzymatic synthesis of the peptide bond of bile acid conjugates by mammalian liver. The further metabolism of... 

The information on the synthesis of amide bonds has served as the basis for the studies of the mechanism of bile acid conjugation. Independently of each other Bremer (1956c), Elliott (1956a,b), and Siperstein and Murray (1956) obtained evidence for the formation of cholyl-fl-CoA as an intermediate in the conjugation reaction. 

A. Factors Contkolling the Synthesis of Bile Acid Conjugation in Patients with Obstructive Jaundice... 

The mechanism,s behind the changes in the synthesis of taurocholic and glycocholic acids in human liver in patients with obstructive jaundice ivas analyzed by Schersten (1967a,b). The following possible explanations for a lower capacity of the synthesis of bile acid conjugates or for an altered conjugation pattern in such cases were provioundcd. 

The facts gathered indicate that in cases with obstructive jaundice the synthesis of bile acid conjugates is inhibited directly by the influence of the retained conjugates on the reaction (product inhibition) and indirectly by an increased mitochondrial hydrolysis of ATP resulting in a relative lack of energy necessary for the conjugation reaction. 

Serum ALP and total bilirubin (unconjugated and conjugated fractions) are traditionally used to monitor cholestatic injury. The ALP families of enzymes are zinc metalloproteases that are present in nearly all tissues. In the liver, ALP is immu-nolocalized to the microvili of the bile canaliculus [124]. Increased synthesis of ALP and its release into the circulation occurs within hours of cholestatic injury [129]. Serum assays of 5 -nucleotidase (5 -NT) or y-glutamyltransferase activity (GGT) are used to confirm the liver as the specific origin for the elevation of ALP. Increases in serum bilirubin or bile acids are usually the result of bile retention subsequent to impaired bile flow, increased production associated with accelerated erythrocyte destruction, or altered bilirubin metabolism [129]. 

Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95 percent) and reused. The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum. They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells. [Note Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood (see p. 179).] The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation (see Figure 18.11). Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g is lost daily in the feces. Approximately 0.5 g per day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine,2 bind bile acids in the gut, prevent their reabsorption, and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. [Note Dietary fiber also binds bile acids and increases their excretion.]... 

Taurine was discovered in 1827 in ox hUe, where it is conjugated with the bile acids. It was later shown to be a major excretory product of the sulfur amino acids methionine and cysteine. Until about 1976, it was assumed that it was a metabolic end-product whose only function was the conjugation of bile acids. In the rat, taurine synthesis accounts for 70% to 85% of total cysteine catabolism. 

---