Conjugation of bile acids

Taurine Osmotic agent in retina and used for conjugation of bile acids dietary essential for cats... 

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. 

Conjugation of bile acids with taurine and glycine. 

V7. Vessey, D. A., The biochemical basis for the conjugation of bile acids with either glycine or taurine. Biochem. J. 174, 621-626 (1978). 

A mechanism for hepatic formation of amino acid conjugates of bile acids developed from early investigations of Siperstein and Murray [37], Bremer [38], and Elliott [39] is summarized as follows ... 

Bremer and Gloor [40] concluded that enzymes for both reactions were present in hepatic microsomes, but recent studies with microsomes of rat [40-42] and human liver [43] have confirmed the presence of only one enzyme, CoA ligase. The assay system, essentially that for long-chain acyl-CoA ligase [42,43], includes 50 mM NaF, a phosphate buffer (pH 7.5), the enzyme preparation, and constituents of Eqn. 1. Product formation was linear up to 12 min with added protein (between 0.1 and 1.2 mg) from a crude microsomal fraction. Sterol carrier protein [44], cysteine or nicotinamide [38,40] were without effect. This rate-limiting enzyme in the two-step sequence catalyzing conjugation of bile acids exhibits a diurnal variation such that the time of maximum enzyme activity coincides with predicted maximum activity of cholesterol 7a-hydroxylase and the time of maximal biosynthesis of bile acids [45]. The enzyme has not been purified. 

The formation of conjugates of taurine or glycine is induced by glucocorticoids, specifically dexamethasone [49]. In primary cultures of rat fetal liver dexamethasone increased and maintained taurine conjugation of cholate, chenodeoxycholate, and deoxycholate short-term cultures of adult rat hepatocytes maintained conjugation of bile acids with glycine and taurine [49]. Enzymatic activity was stimulated by low doses of ethynylestradiol [50], and has been verified in fetal liver [51]. 

The amino acid taurine has been suggested as a marker of hepatotoxicity because it is involved in the conjugation of bile acids to bile acids, the conjugation of xenobiot-ics, and the detoxification of reactive metabolites. Taurine is a product of sulfur acid metabolism and may reflect protein synthesis. The measurement of urinary taurine in models of hepatotoxicity has been described (Sanins et al. 1990 Waterfield et al. 1993a, 1993b, 1993c Timbrell, Seabra, and Waterfield 1995 Waterfield, Asker, and Timbrell 1996), but the measurement is reported to show diurnal variation, wide intraanimal variability, and less success at minor levels of hepatic injury (Maxuitenko, North, and Roebuck 1997). 

Hepatic bile acid production is also changed qualitatively. The conjugation of bile acids with glycine is significantly decreased in liver biopsies from cirrhotic patients (194). However, the ratio of glycine- to taurine-... 

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... 

The conjugation of bile acids with added hydroxylamine by rat liver microsomes in the presence of ATP, CoA, and fluoride to yield bile acid hydroxamates has been used to demonstrate the formation of cholyl-CoA as an intermediate in the enzymatic system catalyzing the synthesis of the natural conjugates (12,13). In pig liver, there appear to be two distinctly different enzyme systems capable of the synthesis of cholylhydroxamic acid (15). A partially solubilized preparation from pig liver catalyzed the rapid formation of cholylhydroxamic acid in the presence of cholic acid and hydroxylamine but in the absence of ATP and CoA. This is in contrast to the synthesis of hydroxamates of bile acids by the microsomes, which required both ATP and CoA. Since fluoride inhibits the system that functions in the absence of ATP and CoA, the reaction appears to be similar to that of a lipase (15)... 

In contrast, in ileal absorptive disorders, Garbutt et al. (38) observed an increase in G T ratios of both cholate and deoxycholate, which was attributed to a decrease in enterohepatic recirculation of taurocholate and deoxycholate. It is also interesting to note that a selective conjugation of cholic acid with L-ornithine could be induced in the rat and guinea pig liver by the injection of a toxic capsular polysaccharide of Klebsiella pneumoniae (39). Partial hepatectomy has also been shown to result in a shutdown in the hepatic synthesis of glycine conjugates of bile acids (40). 

The pKa values of the recently discovered ornithine conjugates of bile acids and of the sulfate esters of glyco- and taurolithocholates have not yet been determined. 

Virtually all markers of peroxisomal function are lipid-boimd or protein-bound they are present in the plasma, but they are not excreted into the urine. Exceptions are the water-soluble glycine-, taurine-, or glucuronic acid conjugates of bile acids which may be found in the urine. The general clinical chemistry lab will not give consistent clues to the existence of peroxisomal disease as there is no readily accessible end product of peroxisomal substrates. 

Hellstrom, K., and J. Sjovall Conjugation of bile acids in patients with h3 othyroidism. J. Atheroscler. Res. 1, 205 (1961). 

---