Chenodeoxycholic acid Subject

The exact contributions of these alternate pathways to total hepatic bile acid synthesis in normal subjects is not certain, although 26-hydroxylation is usually regarded as the major pathway. In addition, it should be pointed out that current views of hepatic cholic acid and chenodeoxycholic acid synthesis are based primarily oh studies carried out in the rat. More recent studies, which have involved the administration of labeled bile acid intermediates to patients, have suggested that bile acid biosynthesis is more complex than previously thought and that multiple pathways exist to convert cholesterol to bile acids (Vll). 

Other clinical signs consist of progressive neurologic dysfunction, cataracts, and premature atherosclerosis (SI). The disease is inherited as an autosomal recessive trait, but is usually only detected in adults when cholesterol and cholestanol have accumulated over many years (S2). Biochemical features of the disease include striking elevations in tissue levels of cholesterol and cholestanol and the presence of unusual bile acids, termed bile alcohols, in bile. These bile alcohols are mainly 5 -cholestane-3a,7a,12a,24S, 25-pentol, Sp-diolestane-3a,7a,12a,23 ,25-pentol and 5P-du)lestane-3a,7a,12a,25-tetrol (S2). As chenodeoxycholic acid is deficient in the bile of patients with CTX, it was postulated that early bile salt precursors are diverted into the cholic acid pathway and 12a-hydroxy bile alcohols with an intact side chain accumulate because of impaired cleavage of the cholesterol side chain and decreased bile acid production (S2). HMG-CoA reductase and cholesterol 7a-hydroxylase activity are elevated in subjects with CTX (N4, N5), so that sufficient 7a-hydroxycholesterol should be available for bile acid synthesis. 

To diagnose CTX, advantage has been taken of the elevated cholestanol levels in plasma. If the ratio of cholestanol to cholesterol is measured by gas-liquid chromatography, a value of over 1% is obtained in patients with CTX compared with less than 0.5% for normal subjects (S2). More recently, capillary gas-liquid chromatography has been used to detect bile alcohol conjugates in the urine of CTX patients and this technique has been useful to assess the efficacy of treatment with orally administered chenodeoxycholic acid (W12). 

As a consequence of the 7a-dehydroxylation process, the bile acid composition of bile in healthy subjects usually comprises around 30 to 40% conjugated cholic acid, 30 to 40% conjugated chenodeoxycholic acid, 10 to 30% conjugated deoxycholic acid, and less than 5% conjugated lithocholic acid, of which the majority is sulfated (H18). 

Using this technique, pool sizes of cholic acid and chenodeoxycholic acid have been estimated to be similar and around 1.0 to 1.5 g each in healthy subjects, with the total bile acid pool amounting to 2 to 4 g (H18, LIO, VIO). Cholic acid turnover is more rapid than for chenodeoxycholic acid, and the rate of hepatic synthesis of cholic acid (300 to 400 mg/day) is therefore approximately double that for chenodeoxycholic acid (150 to 200 mg/day) (H18, VIO). In the steady state, total bile acid synthesis by the liver should equal bile acid loss in the feces, which is around 400 mg/day. Some studies have found that estimates of bile acid synthesis by the isotope dilution technique give values that are higher than those obtained by direct chemical measurement of fecal bile salts (S45), but good agreement has recently been claimed between the two methods (DIO). ITie Lindstedt technique for measuring bile acid turnover and pool size has been modified so that only one bile sample need be collected after intravenous administration of the labeled bile acid. These modified methods measure either pool size alone (D9) or pool size and turnover if both and bile acid are administered at an interval of 24 hours apart (V6). 

The low concentrations of bile acids in urine have also been measured by radioimmunoassay. In one study, total cholic and chenodeoxycholic acid conjugates were measured after extraction and solvolysis to remove sulfate groups, giving a mean urinary excretion of 0.6 p.mol/24 hours for cholic acid and 1.2 p.mol/24 hours for chenodeoxycholic acid in normal subjects (S7). These estimates can be compared with values of 2.1 xmol/24 hours for conjugated cholic acid and 8.4 xmol/24 hours for sulfoglycolithocholic acid obtained for the urinary excretion of bile acids using commercially available radioimmunoassays (WIO). 

The final ratio between cholic acid and chenodeoxycholic acid in bile is influenced also by factors other than the activity of the hepatic 12a-hydroxylase. Thus, the differential rates of enterohepatic cycling, intestinal absorption and degradation are of importance. Ahlberg et al. did not find a correlation between microsomal 12a-hydroxylase activity and the ratio between cholic acid and chenodeoxycholic acid in the bile of some normo- and hyperlipidaemic patients [253]. In a recent in vivo study, Bjorkhem et al. failed to show a correlation between the apparent 12a-hydroxylase activity and the ratio between biliary cholic and chenodeoxycholic acid in healthy subjects and a patient with liver cirrhosis [254]. In this study, a mixture of [ H]7a,12a-dihydroxy-4-cholesten-3-one and [ C]7a-hydroxy-4-choles-ten-3-one was administered intravenously and the relative 12a-hydroxylase activity was calculated from the ratio between and in cholic acid. 

In a single-dose study, 6 healthy subjects were given nitrendipine 10 mg with or without either chenodeoxycholic acid 200 mg or 600 mg, or ursodeoxycholic acid 50 mg. Ursodeoxycholic acid reduced the peak plasma level and AUC of nitrendipine by 54% and 75%, respectively. Chenodeoxycholic acid 200 mg decreased the peak plasma level and AUC of nitrendipine by about 20%, but the 600-mg dose reduced the peak plasma level and AUC of nitrendipine by 54% and 68%, respectively. The reduction in bioavailability of nitrendipine was possibly due to the effects of the bile acids on tablet disintegration or more probably on drug solubilisation. The clinical importance of the interaction is not known. ... 

The primary bile acids are defined as those formed from cholesterol in the liver. Secondary bile acids are those formed from the primary bile acids through the action of intestinal microorganisms during the enterohepatic circulation of bile acids. The secondary bile acids may be subjected to further structural modifications by liver enzymes. The main primary bile acids in most mammalian species are cholic acid and chenodeoxycholic acid.t Other... 

Most bile salts excreted in the feces are of the secondary type. Their formation is discussed in Section VII. The daily fecal excretion of bile salts in healthy subjects is highly variable and easily influenced by dietary alterations. Values from several studies are given in Table VIII. Bile salts virtually disappear from the stools during prolonged fasting, and turnover nearly ceases (19). Primary bile salts appear in the stools of patients with diarrhea (1). Patients taking cholestyramine excrete the usual pattern of secondary bile salts (57), so that apparently bacterial dehydroxylation of bile salts can occur in the presence of this resin. Patients with total external bile fistulas have no bile salts in the feces (2) this does not exclude transintestinal excretion of bile salts but makes it unlikely. As mentioned earlier, the predominance of chenodeoxycholic acid in blood and bile is often reflected in a predominance of lithocholate over deoxycholate in the feces (27). 

In agreement with the findings presented above, the turnover of cholic acid has been reported to be low in patients with hypercholesterolemia (73, 152). Production of cholic and chenodeoxycholic acids has also been shown to be markedly lower in hypercholesterolemic than in triglyceridemic patients, the former subjects exhibiting a smaller cholic but not chenodeoxycholic acid pool than the latter ones (69). 

It seems to be a general observation that the proportion of chenodeoxy-cholic acid is increased in liver cirrhosis. Thus the ratio cholic acid/cheno-deoxycholic acid has been found to be decreased in the bile (23), serum (52,134,193,195-198), and urine (88,199) of cirrhotic subjects. Since the ratios of cholic acid, chenodeoxycholic acid, and deoxycholic acid appear to be approximately the same in bile and serum (200,201), and perhaps also in urine, it seems quite obvious that the bile acid pattern in any of these three sources is similar to that produced by the liver. Simultaneous determinations of bile acids from bile, serum, and urine have not been made, however. The relative increase of chenodeoxycholic acid has been interpreted to indicate a hindrance of 12a-hydroxylation in liver injury when the formation of cholic acid is decreased in favor of chenodeoxycholic acid (202). This, on the other hand, changes the pattern of secondary bile acids so that relatively more lithocholic acid is formed in the colon (191,200,202), the amount of deoxycholic acid being reduced (23,52,134,193,195-198), particularly because quantitatively only a small portion of the bile acids escapes daily from the ileum to the colon (23). 

In another study, Wollenweber et al. (9) determined half-life, pool size, and turnover of cholic and chenodeoxycholic acids in six hypercholesterol-emic patients. Their findings are summarized in Table I. It is apparent that turnover of neither cholic nor chenodeoxycholic acid was affected significantly by administration of nicotinic acid. Failey et al (10) found that the ratio of glycocholamic/taurocholanic acid in seven patients treated with nicotinic acid (2 g/day) fell from 4.0 to 1.7. These authors also reported that subjects given 8 g/day of either benzoic or / -aminobenzoic acid showed changes in these ratios of 1.9 to 3.0 and 2.4 to 0.9, respectively. The available data show that nicotinic acid does not affect bile acid metabolism. 

X = tendon xanthomata, H = homozygous, M = mother, F = father second values after cholestyramine treatment. include fecal bile acids of chenodeoxycholic acid origin values collected from ref. 25-34 bile acids measured in, 22 subjects Two present cases and patients from ref. 26,28,29.°Mainly from... 

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). 

Patients with hypercholesterolemia do not appear to have significant alterations in bile salt synthesis rates, but patients with combined hypercholesterolemia and hypertriglyceridemia have increased synthesis rates for both cholate and chenodeoxycholate (20). Bile salt synthesis rates are not appreciably changed when nicotinic acid feeding lowers plasma cholesterol concentrations (20). Synthesis rates may also be affected by thyroid hormones. Cholic acid synthesis is decreased and half-life prolonged in hypothyroid subjects. These alterations may be corrected with thyroid hormone (21). Bile acid synthesis is increased in thyrotoxicosis (21). 

Urinary excretion of bile salts by healthy subjects is apparently very limited. The urine contained 2 % of the radioactivity administered orally as i C-cholic acid to a healthy subject in whom 100% of the radioactivity was recovered (80) and 0.12% of radioactivity administered to four normal subjects when i C-cholate was given intravenously (25). Conventional methods do not detect bile salts in the urine of healthy subjects (81,82). In jaundice patients, however, bile salts are excreted in the urine regularly (83). The highest 24-hr excretion rates reported by Gregg occurred in patients with common bile duct obstruction (58 mg/24 hr) and drug-induced cholestasis (40 mg/24 hr). The cholate/chenodeoxycholate ratio was greater than 0.59... 

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