Deoxycholic acid Subject

A portion of the primary bile acids in the intestine is subjected to further changes by the activity of the intestinal bacteria. These include deconjugation and 7a-dehydroxylation, which produce the secondary bile acids, deoxycholic acid and hthocholic acid. 

The interest in bile acids as potential carcinogens was subject to investigation as early as 1940 when Cook et al. reported in Nature that repeated injection of deoxycholic acid into the flanks of mice could induce tumour formation in mice." Furthermore, Kelsey and Pienta showed that treatment of hamster embryo cells with lithocholic acid could cause cell transformation. ... 

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). 

Allocholanoic acids (5a-cholanoic acids) are found mainly in lower animals (68,76), but small amounts of allocholic acid (3a,7a,12a-trihydroxy-5a-cholanoic acid), allodeoxycholic acid (3a,12a-dihydroxy-5a-cholanoic acid), and probably also allochenodeoxycholic acid (3a,7a-dihydroxy-5a-cholanoic acid) may be present in bile and feces of mammals (68,76,102). Karavolas et al. (Ill) and Ziller et al. (112) have shown that cholestanol is converted into allocholic acid and allochenodeoxycholic acid in rats with a biliary fistula. The conversion of cholestanol into allocholic acid has also been shown in the rabbit (113). Allodeoxycholic acid is a secondary bile acid, formed from allocholic acid (113,114) and deoxycholic acid (115,116). The early steps in the sequence of reactions from cholestanol to allocholic acid (Fig. 6) have been the subject of two recent investigations. Shefer et al. (17) have shown that the microsomal fraction of rat liver homogenate fortified with NADPH catalyzes 7a-hydroxylation of cholestanol. Bjorkhem and Gustafsson (117) have compared the rates of 7a-hydroxylation of cholestanol,... 

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). 

This well-known bile acid was first reported by Latschinoff in 1885 (26). LatschinofF isolated the compound from ox bile, named it choleic acid, and recognized that it had a lower oxygen content than the trihydroxy acid, cholic acid. One year later Mylius (27, 28) reported an acid from putrefied ox bile which he named deoxycholic acid. Latschinoff (102) and later Lassar-Cohn (103, 104) presented evidence that choleic acid and deoxycholic acid were the same compound, but uncertainty continued until Wieland and Sorge (29) discovered the nature of the molecular complex that is choleic acid. Originally this name was applied to the stable mixture of eight molecules of deoxycholic acid and one molecule of fatty acid but later choleic acids were shown to form between deoxycholic acid and a variety of acholic compounds. The subject of choleic acids was thoroughly reviewed by Sobotka (7) and by Fieser and Fieser (1). 

In normal subject, the predominant ba in serum is chnodeoxy-cholic acid, followed by cholic acid, with a ratio of about 2 1 lithocholic and deoxycholic acid concentrations are lower. 

Fig. 1. Time course of ADP-ribosylation of Rho. 1 ng of recombinant GST-Rho (fusion protein) was incubated with 20 (iM of [ P]-NAD and 3ng of the wild type ( ) or the E173Q (o) mutant of C3 exoenzyme in a total volume of 50 nl of ADP-ribosylation buffer, as described in the text, at 30°C for times indicated. The reaction was terminated by the addition of trichloroacetic acid and Na deoxycholate. After centrifugation, the pellets were subjected to SDS polyacrylamide gel electrophoresis, followed by staining with Coomassie Brilliant Blue and autoradiography. P-ADP-ribosylation of Rho was quantified by cutting out the radiolabeled GST-Rho bands and determining their radioactivities. The relative ADP-ribosylation was expressed as the ratio of the P incorporation into GST-Rho at each point to the maximal P incorporation by the wild type C3 exoenzyme... 

Fig. 3. Autoradiogram of P-ADP-ribosylation of Rho in Swiss 3T3 cell homogenate. Swiss 3T3 cells were treated with buffer alone (lane 1), 30 ng/ml of the wild type (lane 2) or the E173Q mutant (lane 3) of C3 exoenzyme for 72 h in DMEM containing 10 % fetal bovine serum. The cells were washed twice in phosphate-buffered saline (PBS), and incubated with 0.05 % (w/v) trypsin in PBS. The detached cells were collected and suspended in ADP-ribosylation buffer containing [ P]-NAD, followed by sonication. The homogenates were incubated with 100 ng of the wild type C3 enzyme at 30°C for 2 h. The reaction was terminated by the addition of trichloroacetic acid and Na deoxycholate. The pellets were subjected to 12 % SDS polyacrylamide gel electrophoresis and autoradiography. The positions of molecular weight markers are indicated on the left. The position of ADP-ribosylated Rho is indicated by an arrow...

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). 

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