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Bile Cholic acid formation

From the above investigations, summarized in Fig. 2, it was concluded that 7a-hydroxylation of cholesterol may be the first step in the conversion of cholesterol into bile acids, and that 5/S-cholestane-3a,7a,12a-triol probably is an intermediate in cholic acid formation. Since 5)S-cholestane-3a,7a-diol was rapidly converted into chenodeoxycholic acid and only to a small part into cholic acid [19], it was concluded that 5i8-cholestane-3a,7a-diol is a corresponding intermediate in the formation of chenodeoxychohc acid. Samuelsson showed that the conversion of cholesterol into bile acids most probably involves a ketonic intermediate, since [3a- H]cholesterol lost its tritium when converted into chohc acid [1,20]. Since... [Pg.233]

Chimaerol, S S-bufol, 5j8-cyprinol, and scymnol are the 24-, 25-, and 27-hy-droxylated, and 24,27-dihydroxylated derivatives of 27-deoxy-5j8-cyprinol (IX), respectively. It is possible that these naturally occurring bile alcohols could be intermediates in alternative pathways for the formation of choUc acid (XIV) from 27-deoxy-5)8-cyprinol (IX). To test this possibility, these cholestanepolyols were labeled with tritium and given to guinea pigs or rats with a biliary fistula [133-136]. Of the tested bile alcohols, 5)3-chimaerol and 5 -cyprinol were converted efficiently to cholic acid [135,136]. However, these results do not provide conclusive evidence for alternative pathways of cholic acid formation since the conversion of these bile alcohols to cholic acid may merely reflect a lack of specificity of the enzyme systems involved in the conversion of 27-deoxy-5/8-cyprinol (IX) to cholic acid (XIV) via trihydroxy-5)3-cholestanoic acid (XII). [Pg.295]

Bile Acids, Cholecystolithiasis, and Cholestasis 596 Cholic Acid Formation Secondary Bile Acid... [Pg.538]

Based on his examination of the bile salts of various species, Haslewood (1959) had concluded that an evolutionary pattern exists which is reflected in the pathway by which the cholesterol side chain is cleaved to yield the flve carbon acidic side chain of the bile acids. Thus, the older animals (shark) possess a side chain that has a 27 hydroxyl group, the reptiles mainly synthesize a 27 carboxylic acid and mammals a 25 carboxylic acid. Haslewood suggested that 3a, 7a, 12a-tri-hydroxycoprostanic acid might be an intermediate in cholic acid formation in 1952. [Pg.77]

Bile salt export pump (BSEP gene symbol ABCB11) mediates the biliary excretion of nonconjugated bile salts, such as taurocholic acid, glycocholic acid and cholic acid, and therefore is responsible for the formation of the bile acid-dependent bile flow [97, 98]. Its hereditary defect results in the acquisition of PFIC2, a potentially lethal disease which requires liver transplantation [17, 81, 82, 99]. As discussed in Section 12.5.2, the inhibition of BSEP following drug administration may result in cholestasis. [Pg.297]

However, subsequent studies did not find clear evidence to support the view that bile acids could independently stimulate tumour formation utilising rat models. Rather, the findings indicated that bile acids could enhance the effect of other carcinogens in these models. An example of such a study is by McSherry et al. in which male Fischer rats were fed diets supplemented with cholic acid (0.2%) and administered the colonic carcinogen, A-Methyl-A-nitrosurea (MNU), intra-rectally. Fifty-five per cent of MNU treated rats on standard diet developed tumours, a figure that increased to eighty per cent in MNU-treated rats given dietary cholic acid. Rats fed cholic acid supplemented diet alone did not develop tumours. [Pg.73]

Jenkins et al. demonstrated that the secondary bile acid, deoxycholic acid could induce micronuclei formation in the oesophageal adenocarcinoma cell line, OE33. The induction of micronuclei demonstrated a dose-dependent effect and occurred under both neutral and acidic pH conditions. An example of a micronucleus induced by treatment of the OE33 oesophageal adenocarcinoma cell line with deoxy cholic acid is shown in Figure 4.3. [Pg.79]

In the bile cholesterol is kept soluble by fats, phospholipids like lecithin and by bile acids. The important bile acids in human bile are cholic acid, chen-odeoxycholic acid or chenodiol and ursodeoxycholic acid or ursodiol. Bile acids increase bile production. Dehydrocholic acid, a semisynthetic cholate is especially active in this respect. It stimulates the production of bile of low specific gravity and is therefore called a hydrocholeretic drug. Chenodiol and ursodiol but not cholic acid decrease the cholesterol content of bile by reducing cholesterol production and cholesterol secretion. Ursodiol also decreases cholesterol reabsorption. By these actions chenodiol and ursodiol are able to decrease the formation of cholesterolic gallstones and they can promote their dissolution. [Pg.385]

Bouchard G, Yousef IM, Tuchweber B (1993) Influence of oral treatment with ursodeoxycholic and tauroursodeoxy-cholic acids on estrogen induced cholestasis in rats Effects on bile formation and liver plasma membranes. Liver 13 193-202... [Pg.161]

Bile-acid formation in rats involves hydroxylation to give 7a- and 6j8-hydroxy-derivatives. In many cases, no isotope effect was observed on hydroxylation of the appropriate labelled sterol. These examples involve cytochrome P-450 in the oxidation. However, oxidation of [7a- H,24- C]deoxycholic acid or tauro-deoxycholic acid to the corresponding cholic acid showed an isotope effect of 3.8 on examination of recovered starting material. [Pg.216]

The insertion of hydroxyl groups into the 23- or 24-position of 5P-cholestane-3a,7a,12a,25-tetrol was found to be stereospecific. Although all these compounds were potential precursors of bile acid, studies in vivo and in vitro experiments using [3P- H] and (24- C) 5P-cholestane-3a,7a,12a,25-tetrol (46) (Figs.6, 7), (24- C) 5p-cholestane-3a,7a,12a,24R,25-pentol and (24- C) 5P-cholestane-3a,7a,12a,24S,25-pentol demonstrated the existence of a new 25-hydroxylation pathway for the transformation of cholesterol to cholic acid in these patients (2,10). The reaction sequence involved the stereospecific formation of a 24S-hydroxy pentol, 5P-cholestane-3a,7a,12a,24S,25-pentol, 3a7a,12a,25-tetrahydroxy-5P-cholestan-24-one and did not involve SP-cholestanoic acids as intermediates (Fig. 8). The two bile pentols, SP-cholestane-3a,7a,12a,24R, 25-pentol and 5P-cholestane-3a,7a,12a,23R,25-... [Pg.214]

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). [Pg.186]

Microsomal 12a-hydroxylation is the only unique step in the formation of chohc acid and is likely to be of regulatory importance for the ratio between newly synthesized cholic and chenodeoxycholic acid. Introduction of a 26-hydroxyl group seems to prevent subsequent 12a-hydroxylation in rat liver and the 26-hydroxylase could thus also have a regulatory role. It is possible that there are different precursor pools for the synthesis of cholic acid and chenodeoxycholic acid in rats. If so, the relative size of the two pools could be of importance for the relative rate of formation of the two bile acids. [Pg.270]

Mitropoulos et al. have measured the rate of excretion and the specific activities of cholic acid and chenodeoxycholic acid in bile fistula rats fed [ H]cholesterol and infused with [ " C]mevalonate or [ C]7a-hydroxycholesterol [255]. It was concluded that newly synthesized hepatic cholesterol was the preferred substrate for the formation of cholic acid. It could not be excluded, however, that part of the chenodeoxycholic acid had been formed from a pool of cholesterol different from that utilized in cholic acid biosynthesis. The mitochondrial pathway, starting with a 26-hydroxylation, could have accounted for a significant fraction of the chenodeo-... [Pg.271]

The major bile salt of the carp, Cyprinm carpio, is 5a-cyprinol sulfate [21]. When [4- C]cholesterol was injected intraperitoneally into the carp, radioactive 5a-cyprinol was isolated from gallbladder bile [148]. It has been shown that the initial step in the major pathway for the formation of 5a-cyprinol (VI) from cholesterol (XV) is the 7a-hydroxylation of cholesterol to form cholest-5-ene-3j8,7a-diol (XVI) [149] (Fig. 4). It has also been shown that the double bond is isomerized to the A position before being reduced [150]. These in vivo studies suggest that until the intermediary formation of a A compound, presumably 7 ,12a-dihydroxycholest-4-en-3-one (XVII), the sequence of reactions in the biosynthesis of 5 -cyprinol (VI) in the carp is the same as that in the conversion of cholesterol (XV) to cholic acid (XIV) in mammals. 7a,12a-Dihydroxycholest-4-en-3-one (XVII) was found to be converted into 5a-cholestane-3a,7a,12a-triol (XVIII) by the microsomal fraction of carp hver fortified with NADPH [151]. The conversion of the triol (XVIII) to 5a-cyprinol (VI) via 27-deoxy-5a-cyprinol (XIX) was also established. The 26-hydroxylation of the triol (XVIII) was catalyzed by the microsomal fraction fortified with NADPH, and the 27-hydroxylation of 27-deoxy-5a-cyprinol (XIX) was catalyzed by the mitochondrial fraction fortified with NADPH [151]. [Pg.296]

In the in vivo studies with labeled cholesterol [33] as well as mevalonate [157], the label was incorporated into the minor bile acids of the toad, cholic acid (XIV) and 3a,7a,12a-trihydroxy-5y3-cholestan-26-oic acid (X). In contrast, the major bile acids, 3a,7 ,12 -trihydroxy-5/3-cholest-22-ene-24-carboxylic acid and 3a,7a,12a-trihy-droxy-5)8-cholest-23-en-26-oic acid, did not become labeled and their biochemical origin is still obscure. The formation of labeled cholic acid and trihydroxy-5j8-cholestanoic acid suggests that in the toad 27-deoxy-5j8-cyprinol (VIII) is converted to cholic acid (XIV) via the C27 bile acid (X) by the same pathway as that in mammals. [Pg.298]

Early work in vitro on the sequence of reactions in the conversion of cholesterol into bile acids was carried out with mitochondrial preparations from rat and mouse liver (11). These preparations were found to catalyze predominantly reactions involving the oxidation of the side chain of C27-steroids. No evidence for the formation of 12a-hydroxylated metabolites was obtained. In 1963, Mendelsohn and Staple (12) reported the conversion of cholesterol into 5/ -cholestane-3a,7a-12a-triol in the presence of a 20,000 supernatant fluid of rat liver homogenate. This finding provided the first experimental evidence for the long surmised role of 5/ -cholestane-3a,7a,12a-triol as an intermediate in the conversion of cholesterol into cholic acid. Subsequent work with this enzyme preparation and subfractions of it has led to the elucidation of the sequences of reactions in the conversion of cholesterol into 5/ -cholestane-3a,7a,12a-triol (Fig. 1). [Pg.3]


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See also in sourсe #XX -- [ Pg.596 ]




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