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Biomedical subjects

R Lester

Publications and source records attributed to R Lester.

174 records · Page 10Linked to original sources
PubMedDate not supplied

Bile acid metabolism in the fetus and newborn.

The development of bile acid synthesis, secretion and absorption was studied in laboratory animals and humans. Although there is species variation, a developmental pattern emerges. Bile acid pool size and synthesis rates increase during the final third of gestation and the perinatal period. Similarly, bile acid secretion is a developing function during the final third of gestation and is incompletely developed at birth. The ileal mechanism for active bile acid transport is absent at birth and only develops during the first 2--5 weeks or more of life. It is therefore possible that the intestinal conservation of bile acid is ineffective in the newborn. The combination of immaturity of bile acid synthesis, secretion and absorption probably contributes to the fat malabsorption especially evident in low birth weight infants. Finally, synthesis, secretion and absorption can be induced to develop early by the administration of adrenocortical steroid. The induction of mechanisms for bile acid metabolism raises the possibility of therapeutic intervention in severe cases of neonatal malabsorption of lipid.

Aging↗
PubMedDate not supplied

Metabolism of 24-norlithocholic acid in the rat: formation of hydroxyl- and carboxyl-linked glucuronides and effect on bile flow.

24-Norlithocholic (3 alpha-hydroxy-24-nor-5 beta-cholan-23-oic) acid is the lower homologue of lithocholic acid, a potent cholestatic agent. In order to characterize its cholestatic potential and metabolic fate, 3 beta-tritiated 24-norlithocholate was infused intravenously into adult male Sprague-Dawley rats prepared with an external biliary fistula. The results demonstrate that 24-norlithocholate does not induce cholestasis in rats when administered in doses in excess of those necessary for lithocholate to produce cholestasis. Hydroxyl- and carboxyl-linked glucuronides were identified as major metabolites secreted in the bile. Especially noteworthy is the identification of carboxyl-linked glucuronides of mono-, di- and trihydroxylated C23 bile acids. Their total amount (25% of recovered radioactive products) is comparable to that of the hydroxyl-linked glucuronide of 24-norlithocholic acid (41%). In this study, for the first time, a bile acid diglucuronide, substituted both at 3-hydroxyl and carboxyl groups, was detected (11%).

Animals↗
PubMedDate not supplied

Bile salts induce calcium uptake in vitro by human erythrocytes.

At high concentrations, bile salts induce hemolysis by comicellization of lipid components of the cell membrane. However, bile salts are also associated with hemolysis at lower concentrations by mechanisms which have not been characterized. To investigate the possibility that bile salts promote calcium uptake by red blood cells and that bile salt-associated hemolysis is, in part, calcium-mediated, calcium uptake by red blood cells was measured in the presence of individual bile salts, and hemolysis dependence upon calcium availability was examined. Washed human red blood cells with or without ATP depletion were incubated with 1 mM CaCl2 and tracer amounts of 45CaCl2 in the presence of selected bile salts at concentrations (0.01 to 0.3 mM) reported to be below critical micellar concentrations. Calcium uptake (defined for the purposes of this study as 45Ca retained in red blood cells) was monitored over 5 hr, after which hemolysis and membrane phospholipid content were determined. The presence of bile salts stimulated calcium uptake 4- to 25-fold--the magnitude of which was partly related to the lipid solubility of the bile salts. ATP depletion or exposure to trifluoperazine, procedures which inhibit calcium pump activity in red blood cells, enhanced bile salt-induced calcium uptake relative to controls. The percentage of associated hemolysis (2 to 14%) at the end of 5 hr correlated directly with the observed calcium uptake. Removal of calcium from the extracellular space reduced hemolysis in the presence of bile salts to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile Acids and Salts↗
PubMedDate not supplied

Hepatotoxic bile acids increase cytosolic Ca++ activity of isolated rat hepatocytes.

Effects of bile acids on cystolic Ca++ activity and cell viability of isolated rat hepatocytes were studied to test the hypothesis that bile acids may produce hepatotoxicity by increasing cystolic Ca++ activity. Changes in cystolic Ca++ activity were calculated from time-dependent changes in fluorescence of quin-2 loaded hepatocytes. Release of lactate dehydrogenase and changes in propodium iodide fluorescence were used to assess cell viability. Bile acids studied were unconjugated and taurine-conjugated cholate, chenodeoxycholate (and taurochenodeoxycholate), deoxycholate (and taurodeoxycholate) and lithocholate (and taurolithocholate). With the exception of cholate and taurocholate, bile acids increased cystolic Ca++ activity within 10 to 30 sec in a concentration-dependent fashion (0.05 to 1.0 mM) and in the order lithocholate = taurolithocholate greater than chenodeoxycholate = taurochenodeoxycholate = deoxycholate = taurodeoxycholate. The initial increase in cystolic Ca++ activity by bile acids was not due to cell damage, since bile acid-induced decreases in cell viability were not significant until 2 to 3 min. At higher concentrations of unconjugated bile acid, there was a secondary increase in quin-2 fluorescence corresponding temporally to the increase in propodium iodide fluorescence, indicating cell damage after the initial increase in cystolic Ca++ activity. The ability of conjugated and unconjugated bile acids to increase cystolic Ca++ activity was abolished and decreased (60 to 90%), respectively, in the absence of extracellular Ca++, indicating that extracellular Ca++ is the major source of the bile acid-induced increase in cystolic Ca++ activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Biliary copper excretion in the rat is enhanced by spironolactone.

Tissue distribution and excretion (urinary, fecal, and biliary) of an intravenous bolus of 64Cu(NO3)2 were measured in rats pretreated with spironolactone and in controls. Intact animals pretreated with spironolactone excreted 10% more of a standard intravenous injection of copper in the first 24 hr than did controls. At the end of that time, kidney, red blood cell, and serum copper levels all were similar for the two groups, but liver copper concentrations were higher in controls. During the 1st hr after copper injection, plasma copper levels tended to fall more rapidly in pretreated animals, whereas liver copper concentrations increased more rapidly; red blood cell copper concentrations were not higher in animals given spironolactone. Pretreated animals excreted significantly more copper in the bile during the first 2 hr after 64Cu(NO3)2 injection, and had higher hepatic copper levels at 3 hr.

Animals↗
PubMedDate not supplied

Glucuronidation of monohydroxylated short chain bile acids by human liver microsomes and purified human liver UDP-glucuronosyltransferases.

The glucuronidation of monohydroxylated bile acids and their analogs with a shortened side chain (short-chain bile acids) by human liver microsomes and by two UDP-glucuronosyltransferases purified therefrom has been studied in vitro. In microsomes, all 18 substrates tested underwent glucuronidation; the rate of reaction and the site of attachment of glucuronic acid (hydroxyl group in position 3, side chain carboxyl group, or various ratios of both products) were strongly dependent on the length of the side chain, the configuration of the 3-hydroxyl group, and the configuration of the A/B ring junction (5 alpha-H/5 beta-H). Two UDP-glucuronosyltransferases (UDPGTs) purified from human microsomes, designated "pl 7.4" and "pl 6.2" according to their behavior in chromatofocusing, accounted for the formation of hydroxyl-linked glucuronides of a different pair of bile acids each. The pl 7.4 human liver UDPGT catalyzed the glucuronidation of C20 and C22 with the 3 alpha-OH, 5 beta-H configuration, while the pl 6.2 human liver UDPGT catalyzed the glucuronidation of either 3-OH epimer of C21 and C24 acids with the 5 alpha-H configuration. The enzymes displayed a relatively high selectivity in that they did not accept any of the remaining 14 bile acids as substrates; none of the enzymes led to the formation of a carboxyl-linked glucuronide. In addition, purified human liver UDPGT did not catalyze the glucuronidation of cholate, deoxycholate, chenodeoxycholate, ursodeoxycholate, lithocholate, hyocholate, hyodeoxycholate, bilirubin, morphine, or 4-hydroxybiphenyl. The above results suggest that several bile-acid UDP-glucuronosyltransferases of high specificity exist in human liver.

Bile Acids and Salts↗