Estimation of Mouse Tumour Blood Volumes employing a Radioactive Isotope Technique

Stewart, F. S.; Pearson, A. E. G.

doi:10.1038/186250b0

Cited by 7 publications

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“…39 DCA and LCA are reconjugated with glycine and taurine, accumulated in hepatocytes, and released to the blood pool through BA efflux transporters, leading to significantly increased GLCA, TLCA, GDCA, and TDCA levels in serum. It is well known that the LCA and its conjugates are cirrhogenics 40 and may induce intrahepatic cholestasis in a variety of experimental animals. 41 This could set up a vicious circle in which the increase in serum LCA conjugates, TLCA and GLCA, determines further hepatic damage.…”

Section: Discussionmentioning

confidence: 99%

Serum Bile Acids Are Associated with Pathological Progression of Hepatitis B-Induced Cirrhosis

et al. 2016

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Recent metabonomic studies have identified an important role of bile acids in patients with liver cirrhosis. Serum bile acids, such as glycocholate (GCA), glycochenodeoxycholate (GCDCA), taurocholate (TCA) and taurochenodeoxycholate (TCDCA), increased significantly in liver cirrhosis patients. Our recently published urinary metabonomic study showed that glycocholate 3-glucuronide, taurohyocholate, TCA, glycolithocholate 3-sulfate and glycoursodeoxycholate (GUDCA) were markedly increased in hepatitis B-induced cirrhotic patients (n = 63) compared with healthy controls (n = 31). The urinary levels of GUDCA were able to differentiate among three stages of cirrhotic patients with Child Pugh (CP) score A, B and C. In this study, we recruited two new cohorts of patients with hepatitis B-induced cirrhosis and healthy control subjects and quantitatively profiled their serum bile acids using ultra performance liquid chromatography triple quadrupole mass spectrometry. Serum bile acid profile and corresponding differential bile acids were characterized, in addition to the blood routine, liver and renal function tests. The alterations of bile acids contributing to the inter-group variation between healthy controls and cirrhotic patients, and among pathological stages of CP grade A, B and C were also investigated. Five bile acids, GCA, GCDCA, TCA, TCDCA and GUDCA were significantly altered among different stages of liver cirrhosis (n = 85), which was validated with an independent cohort of cirrhotic patients (n = 53). Our results show that dynamic alteration of serum bile acids is indicative of an exacerbated liver function, highlighting their potential as biomarkers for staging the liver cirrhosis and monitoring its progression.

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Section: Discussionmentioning

confidence: 99%

Serum Bile Acids Are Associated with Pathological Progression of Hepatitis B-Induced Cirrhosis

et al. 2016

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Inhibition of hepatic and extrahepatic glutathione S-transferases by primary and secondary bile acids

Hayes¹,

Mantle²

1986

Biochemical Journal

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Glutathione S-transferases are a complex family of dimeric proteins that play a dual role in cellular detoxification; they catalyse the first step in the synthesis of mercapturic acids, and they bind potentially harmful non-substrate ligands. Bile acids are quantitatively the major group of ligands encountered by the glutathione S-transferases. The enzymes from rat liver comprise Yk (Mr 25 000), Ya (Mr 25 500), Yn (Mr 26 500), Yb1, Yb2 (both Mr 27 000) and Yc (Mr 28 500) monomers. Although bile acids inhibited the catalytic activity of all transferases studied, the concentration of a particular bile acid required to produce 50% inhibition (I50) varies considerably. A comparison of the I50 values obtained with lithocholate (monohydroxylated), chenodeoxycholate (dihydroxylated) and cholate (trihydroxylated) showed that, in contrast with all other transferase monomers, the Ya subunit possesses a relatively hydrophobic bile-acid-binding site. The I50 values obtained with lithocholate and lithocholate 3-sulphate showed that only the Ya subunit is inhibited more effectively by lithocholate than by its sulphate ester. Other subunits (Yk, Yn, Yb1 and Yb2) were inhibited more by lithocholate 3-sulphate than by lithocholate, indicating the existence of a significant ionic interaction, in the bile-acid-binding domain, between (an) amino acid residue(s) and the steroid ring A. By contrast, increasing the assay pH from 6.0 to 7.5 decreased the inhibitory effect of all bile acids studied, suggesting that there is little significant ionic interaction between transferase subunits and the carboxy group of bile acids. Under alkaline conditions, low concentrations (sub-micellar) of nonsulphated bile acids activated Yb1, Yb2 and Yc subunits but not Yk, Ya and Yn subunits. The diverse effects of the various bile acids studied on transferase activity enables these ligands to be used to help establish the quaternary structure of individual enzymes. Since these inhibitors can discriminate between transferases that appear to be immunochemically identical (e.g. transferases F and L), bile acids can provide information about the subunit composition of forms that cannot otherwise be distinguished.

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The importance of keeping bile salts in their place.

Heaton¹

1969

Gut

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Bile contains several substances which are partially absorbed from the intestine and secreted again in the bile. They include urobilinogen, cholesterol,1 and possibly certain hormones2 and fat-soluble vitamins3. But the enterohepatic circulation of bile salts is unique in both its physiological importance and its efficiency.Conjugated bile salts have powerful detergent properties,4 which are important in stabilizing the supersaturated state of bile and in promoting fat digestion and absorption.5 These functions, and the complex metabolism undergone by bile salts, all take place in the context of the enterohepatic circulation and depend on its proper functioning. The enterohepatie circulation may be thought of as an endless flow of detergent through thc liver, biliary tract, small and to some extent large, intestine, and back to the liver again. Thanks to the gallbladder, this process occurs in bursts rather than continuously and it is estimated that the bile salt pool recirculates twice with each meal, or up to eight times a-day.6 The normal pool size being 3 to 4 g,7 this means that about 24 g of bile salts enters the duodenum each day. A striking feature of the enterohepatic circulation is its efficiency as a closed recycling system. Probably more than 99 % of the bile salts in the body are within the enterohepatic circulation at all times. The systemic blood contains less than 10 mg in all8 and none is detectable in the urine.9 A significant leak does occur into the stools, but the normal daily excretion of 15 to 20% of the pool represents a mere 3 to 4% escape at each turn of the cycle.10' 11 The efficiency of the enterohepatic circulation depends on several factors. First, the liver is avid in extracting bile salts from the blood.12 Isotope studies show the mean half-life of plasma cholic acid to be only 12-6 minutes.13 Such rapid clearance must be due to an active transport system, since it involves transfer of large polar molecules across the essentially lipid membrane of the liver cell.14 The same is true of biliary secretion which is also rapid.14 Labelled bile salt has been detected in the duodenum of a cholecystectomized patient within 20 minutes of intravenous injection.15 Secondly, having reached the duodenum, bile salts are prevented from regurgitating into the stomach by the competence of the pyloric sphincter. In normal subjects they are either undetectable or present in only trace amounts in the gastric juice.16 Thirdly, due to their low pKa, conjugated bile acids exist mainly in the ionized form at the pH of the upper small intestinal lumen.4 This minimizes any tendency to diffuse down electrochemical gradients into the blood or lymph17 and ensures that the intraluminal concentration remains high until fat absorption is complete.18 This physicochemical 'seal' depends upon bile salts remaining in the conjugated state, since free bile acids readily diffuse out of the jejunal lumen.17Deconjugation is within the capacity of many intestinal bacteria,'9 so that a fourth factor in maintaining the ef...

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Estimation of Mouse Tumour Blood Volumes employing a Radioactive Isotope Technique

Cited by 7 publications

References 1 publication

Serum Bile Acids Are Associated with Pathological Progression of Hepatitis B-Induced Cirrhosis

Serum Bile Acids Are Associated with Pathological Progression of Hepatitis B-Induced Cirrhosis

Inhibition of hepatic and extrahepatic glutathione S-transferases by primary and secondary bile acids

The importance of keeping bile salts in their place.

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