Deoxycholate inhibition

J. D. Martinez, E. D. Stratagoules, J. M. LaRue, A. A. Powell, P. R. Gause, M. T. Craven, C. M. Payne, M. B. Powell, E. W. Gerner and D. L. Earnest, Different bile acids exhibit distinct biological effects the tumour promoter deoxycholic acid induces apoptosis and the chemopreventive agent ursodeoxycholic acid inhibits cell proliferation, Nutr. Cancer, 1998, 31(2), 111. 

E. Im and J. D. Martinez, Ursodeoxycholic acid (UDCA) can inhibit deoxycholic acid (DCA)-induced apoptosis via modulation of EGFR/ERK signalling in human colon cancer cells, J. Nutr., 2004, 134, 483. 

The enzyme in the myocardium has recently attracted attention because of the possibility that adenosine is a physiological regulator of coronary blood flow (67) (adenosine is a potent coronary dilator). Most of the 5 -nucleotidase activity in rat heart is membrane bound, and a partially purified preparation has been obtained by extracting acetone powder preparations with deoxycholate (68). All 5 -nucleotides are hydrolyzed. The enzyme is strongly inhibited competitively by ATP (Ki 1.8 fxM). Whether this provides a regulatory mechanism for adenosine formation in the heart is not known. 

In 1954, Beaufay and de Duve (27) first suggested a relationship between microsomal phospholipid and glucose-6-phosphatase. They observed a loss of enzymic activity from phospholipid-rich microsomal preparations concomitant with extraction with such organic solvents as butanol or treatment with lecithinase. Various studies were carried out to demonstrate that the latter effect was not produced through inhibition of enzymic activity by accumulated products of the hydrolysis of phospholipids. On the basis of their observations that deoxycholate treatment labilized microsomes to phospholipase action, they concluded that . . . the detergent did not exert its primary effect on the dissociation of phospholipids from microsomal protein, but that it probably disrupted... 

Detergents (26, 41, 46, 96, 97) Optimal concentrations of deoxycholate, cholate, Triton X-100, and cetyltri-methylammonium bromide activate, as does urea. Activation of phosphotransferase > that of phosphohydrolase. Supraoptimal levels inhibit, as do all tested concentrations of sodium lauryl sulfate and Tweens 20 and 80. (See also Lysolecithin, Fatty acids, and Long-chain fatty acyl-CoA esters, above)... 

Phlorizin (7, 13, 16, 17, 89, 101, 146) Inhibits noncompetitively both phosphohydrolase and phosphotransferase activities inhibition of former potentiated by cetrimide and abolished or significantly ameliorated by deoxycholate, cholate, Triton X-100, or digitonin treatment of microsomes. Cetrimide reduces inhibition by phlorizin of phosphohydrolase... 

The fructosyltransferase from A. aculeatus displayed activity without the addition of any metal ions. However, some effects were observed in its susceptibUity to mono- and divalent cations [33]. For ejample, Mn, K, and Co caused a 1.4—1.9-fold increase in the activity, whereas low concentrations of Hg and Zn produced 35-60% inhibition. It was also found that the enzyme was slightly activated by several non-ionic and anionic surfactants such as sodium dodecylsulphate (1.5-fold at lOmM), sodium deoxycholate (1.4-fold at ImM), and Triton X-100 (1.4-fold at 5% w/v). Moreover, it was resistant to low concentrations (1-lOmM) of reducing agents such as dithiothreitol and P-mercaptoethanol. 

H-12) Gallstones. Most gallstones are composed mainly of cholesterol. Bile salts and phospholipids normally prevent the precipitation of cholesterol, but cholesterol stones may form when the cholesterol/bile salt-phospholipid ratio increases excessively. Cheno-deoxycholate may be used as oral therapy for cholesterol gallstones. It not only provides an extra recirculating source of bile acids but inhibits the rate-limiting step in cholesterol biosynthesis. 

Bile salts Sodium deoxycholate Sodium glycocholate Sodium taurocholate Formation of reverse micelles, solubilization of proteins/peptides Removal of epithelial cells and formation of transient pores Inhibition of proteolytic activity Reduction of mucus viscosity... 

All main bile salts (glyco- and taurocholate, deoxycholate and chenodeoxycho-late) have the same effects on HGL activity which increases up to a bile salt concentration of around 3 mM for a single species and 4 mM for a mixture of bile salts. However, it is worth noting that synthetic detergents (Triton X-100, Tween, benzalkonium chloride) that dramatically decrease surface tension (<8mN/m), actually inhibit HGL. 

Rodrigues, C.M., Fan, G., Wong, P.Y., Kren, B.T., and Steer, C.J. (1998) Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production. Molecular Medicine, 4 (3), 165-178. 

Sussman, M.L. Hays, J.B. Smith, T.A.G. Selective, reversible inhibition of the lactose phosphotransferase system of Staphylococcus aureus by dodecyl sulfate and deoxycholate. Arch. Biochem. Biophys., 182, 134-137 (1977)... 

Only a definite scope of monomers can be polymerized in a given host. This indicates that inclusion polymerization displays a sterically different boundary condition from other polymerizations. That is, an increase of one methylene unit of one monomer can induce an inhibition of the polymerization in a given channel (Fig. 5a,b). Moreover, the relative sizes of the channels change the polymerizabilities of the identical monomers. Even though a monomer does not polymerize in a small channel, the same monomer polymerizes in a larger channel, (Fig. 5b,c). For example, 4-methyl-1,3-pentadiene polymerized in the smaller channels of deoxycholic acid. 

Mosbach and Bevans (134) showed that cholestanol-induced cholecystitis and cholelithiasis could be inhibited by the simultaneous administration of dehydrocholic acid and that the extent of inhibition depended on the relative concentrations of the two steroids. Similar observations were made by Ricci et al, (135). Deoxycholic and cholic acids were also effective inhibitors (136), but hyodeoxycholic acid did not suppress gallstone formation and appeared to increase biliary tract inffammation. Several non-bile acid choleretics were without inhibitory effects (136). Lindelof and van der Linden (32) found that intravenous injections of cholecystokinin every 8 hr did not suppress and may actually have enhanced gallstone formation. The inhibition of cholelithiasis by dehydrocholic, deoxycholic, and cholic acids was not accompanied by a decrease in cholestanol absorption but did result in increased tissue cholestanol levels, suggesting a decrease in the conversion of this sterol to bile acids (134,136). Conversely, methyl testosterone apparently inhibited stone formation by interfering with cholestanol absorption, since tissue and serum levels of cholestanol were reduced (137). Olive oil has been shown to facilitate stone formation (138), perhaps by enhancing cholestanol absorption (137). 

The reason for the low bile acid formation in familial hypercholesterolemia is not known. It could be due to impaired availability of cholesterol to the pool which is utilized for bile acid synthesis, a partial deficiency or inhibition of the enzyme system producing bile acids, deficient hepatic secretion of bile acids, or augmented intestinal reabsorption. An interesting observation is that the bile of hypercholesterolemic patients may contain relatively little or no deoxycholic acid (23,73,157), a finding recorded also in patients... 

Norman (3) demonstrated that the types of bile acids found in normal rat bile were not the same as those which were excreted in the feces. However, when the rats were fed high levels of antibiotics, the fecal bile acids were excreted essentially unchanged from the biliary bile acids (4). The intestinal bacteria were responsible for the hydrolysis of the biliary taurine-conjugated bile acids to the free bile acids found in the feces. Norman also showed that the dehydroxylation of cholic acid to deoxycholic acid could be prevented by Inhibiting the intestinal bacteria. The total amount of fecal bile acid excreted by conventional chicks has been found to be significantly lowered (5) by incorporation of an antibiotic into the diet. 

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