Bile acid sulfates metabolism

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). 

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. 

Fernandes and A. van Zanten, Cholestatic effects of sulfated bile acids in "Sulfate Metabolism and Sulfate Conjugation," G.J. Mulder, J. Caldwell, G.M.J. van Kempen and R.J. Vonk, eds., Taylor Francis, London (1982). 

Finally, the fact that anthocyanins can reach the brain represents a beginning of an explanation of the purported neuroprotection effects of anthocyanins. Anthocyanins may be eliminated via urinary and biliary excretion routes. " The extent of elimination of anthocyanins via urine is usually very low (< 0.2% intake) in rats and in humans, indicating either a more pronounced elimination via the bile route or extensive metabolism. As mentioned earlier, in the colon, non-absorbed or biliary excreted anthocyanins can be metabolized by the intestinal microflora into simpler break-down compounds such as phenolic acids that may be (re)absorbed and conjugated with glycine, glucuronic acid, or sulfate and also exhibit some biological... 

The steroid hormones are mainly inactivated in the liver, where they are either reduced or further hydroxylated and then conjugated with glucuronic acid or sulfate for excretion (see p. 316). The reduction reactions attack 0X0 groups and the double bond in ring A. A combination of several inactivation reactions gives rise to many different steroid metabolites that have lost most of their hormonal activity. Finally, they are excreted with the urine and also partly via the bile. Evidence of steroids and steroid metabolites in the urine is used to investigate the hormone metabolism. 

Most hormones have a half-life in the blood of only a few minutes because they are cleared or metabolized very rapidly. The rapid degradation of hormones allows target cells to respond transiently. Polypeptide hormones are removed from the circulation by serum and cell surface proteases, by endocytosis followed by lysosomal degradation, and by glomerular filtration in the kidney. Steroid hormones are taken up by the liver and metabolized to inactive forms, which are excreted into the bile duct or back into the blood for removal by the kidneys. Catecholamines are metaboli-cally inactivated by O-methylation, by deamination, and by conjugation with sulfate or glucuronic acid. 

PCB arene oxides can also generate dihydrodiols via a hydrolytic pathway mediated by microsomal epoxide hydrolase, although metabolism to monohydroxy-metabolites is more commonly observed [74,75]. OH-PCBs are susceptible to further metabolism, i. e. conjugation reaction with glucuronic acid or sulfate, which increases the water solubility and facilitates excretion. Glucuronic acid and sulfate conjugates of several PCB congeners have been determined in bile and urine from experimental animals exposed to the PCBs [50,76,77]. Biliary excretion is the preferred pathway for PCB metabolites, whereas only a small portion is excreted via the urine [77]. 

Palmer [56-58] first reported the presence in human bile of a sulfate ester of lithocholate in as much as 40-80% of the small amounts of available glyco- and taurolithocholate. Following intragastric or intraduodenal intubation of glyco-[24- C]lithocholic acid 3-sulfate to rats with bile fistulas, 70-89% of the radioactivity was recovered in bile [59] allolithocholate 3-sulfate was also reported in rat bile [60]. The radioactive conjugate was absorbed intact without loss of the sulfate, and was not metabolized in the liver (e.g., to the muricholates or chenodeoxycholate) [58,59]. Similarly, chenodeoxycholate 3-sulfate was not metabolized after intravenous infusion into rats or hamsters with or without obstruction of the biliary tract [58,59,61]. Lithocholate 3-sulfate is efficiently removed from the body [62]. 

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