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Biomedical subjects

R Lester

Publications and source records attributed to R Lester.

At least 55 records · Page 3Linked to original sources
PubMed1985

Excretion of cholate glucuronide.

[3-3H]Cholic acid glucuronide [7 alpha,12 alpha-dihydroxy-3 alpha-O-(beta-D-glucopyranosyluronate)-5 beta- cholan-24-oate] was synthesized and administered to rats prepared with either an external biliary fistula or a ligated bile duct. When bile fistula animals were given either microgram or milligram amounts of the glucuronide, biliary secretion of label was rapid and efficient: greater than 90% of the administered label was secreted within 60 min and total recovery of label in bile was 98.6 +/- 1.2%. Studies in which [14C]taurocholate was included in the dose indicated that this bile acid was secreted into bile significantly more rapidly than was the glucuronide. In animals with ligated bile ducts, urinary excretion was the major route of elimination: after 20 hr, 83.4 +/- 9.3% of the administered dose had been excreted in urine. Urinary excretion of cholate glucuronide was significantly more rapid than that of taurocholate. Gas-liquid chromatographic analysis of the methyl ester acetate derivatives of labeled compounds isolated from bile and urine by chromatography established that the bulk (greater than 70%) of the administered material was secreted in bile or excreted in urine as the intact cholate glucuronide. From these results, we conclude that the glucuronidation of cholic acid produces a derivative which is rapidly and effectively cleared from the circulation and excreted.

Animals↗
PubMed1984

Calcium binding by lithocholic acid derivatives.

Lithocholic acid (LCA) and its sulfate (LCS) and glucuronide (LCG) derivatives are potent cholestatic agents. During the course of LCG-induced cholestasis in rats, calcium (Ca) salts of LCG precipitate in bile. To characterize the affinity of bile salts for Ca, solutions of selected bile salts were titrated with Ca. Apparent equilibrium constants (KcaBS) were determined from the unbound Ca ion concentrations that were measured spectrophotometrically with metallochromic indicators antipyrylazo III or murexide or with a Ca-selective electrode. KCaBS values were 1.12 +/- 0.04 X 10(-4) M for LCS, 2.88 +/- 0.26 X 10(-4) M for LCG, 3.09 +/- 0.21 X 10(-4) M for LCA, 1.93 +/- 0.07 X 10(-3) M for taurocholic acid (TC), 2.69 +/- 0.08 X 10(-3) M for glycocholic acid (GC), and 6.07 +/- 0.27 X 10(-3) M for taurolithocholic acid sulfate (TLCS). The KCaBS for LCG measured by a Ca-selective electrode under identical conditions was 5.53 +/- 2.75 X 10(-4) M. Comparing relative cholestatic potential with affinity for Ca, cholestatic bile salts LCS, LCG, and LCA bind Ca 10-60 times more avidly than TC, GC, and TLCS. At the unbound Ca ion concentrations of serum or bile (approx 1 mM), only LCS, LCG, and LCA would be expected to bind significant amounts of Ca.

Animals↗
PubMed1984

Lithocholate glucuronide is a cholestatic agent.

Lithocholic acid and its taurine, glycine, and sulfate derivatives are potent cholestatic agents. Lithocholate glucuronide is present in the plasma and urine of patients with cholestatic syndromes, but little is known of its metabolism, excretion, and cholestatic potential. [3 beta-3H]lithocholate 3-O-beta-D-glucuronide was synthesized, and chemical and radiochemical purity were established. The aqueous solubility of lithocholate glucuronide was determined and found to be greater than that of lithocholic acid or several of its derivatives. In the range of concentrations examined, calcium ions precipitated lithocholate glucuronide stoichiometrically. The material was administered to rats prepared with an external biliary fistula. When 17-25 micrograms quantities were administered, 89.1 +/- 4.5% (mean +/- SEM) of the radiolabel was secreted in bile within the first 20 h after administration, the major fraction being secreted in less than 20 min. Four-fifths of the radiolabeled material in bile was the administered unaltered parent compound, while a minor fraction consisted of a more polar derivative(s). We showed that increasing biliary concentrations of more polar derivatives were observed with milligram doses of [3H]lithocholate glucuronide, and with time after the administration of these loading doses. Milligram doses of [3H]lithocholate glucuronide resulted in partial or complete cholestasis. When induced cholestasis was partial, secretion in bile remained the primary excretory route (82.5-105.6% recovery in bile), while, when complete cholestasis was induced, wide tissue distribution of radiolabel was observed. Cholestasis developed rapidly during infusion of [3H]lithocholate glucuronide. Bile flow was diminished within 10-20 min of the start of an infusion of 0.05 mumol, 100 g-1 body weight, minute-1, administered concomitantly with an equimolar infusion of taurocholate. The results establish that lithocholate glucuronide exerts cholestatic effects comparable to those exerted by unconjugated lithocholic acid.

Animals↗
PubMed1983

Constituents of human meconium--I. Identification of 3-hydroxy-etianic acids.

The monohydroxylated fraction of bile acids of human meconium was analyzed by capillary GC-MS. In the sulfate-glucuronide fraction three saturated, and one unsaturated C20 steroidal acids were found. These acids were identified as 3 alpha-hydroxy-5 alpha-, 3 alpha-hydroxy-5 beta-,3 beta-hydroxy-5 alpha-androstane-17 beta-carboxylic, and 3 beta-hydroxyandrost-5-ene-17 beta-carboxylic based on the unequivocal GC-MS comparison with standards of all possible epimers at C-3, 5 and 17. The amount of the major C20 acid, 3 alpha-hydroxy-5 alpha-androstane-17 beta-carboxylic, in meconium was 0.2 nmol/g, i.e. 5 to 10 times the amount of lithocholic acid. To prevent the oxidation of 21-hydroxy-20-oxopregnanes to C20 acids meconium was extracted in the presence of sodium borohydride. In the absence of this reducing agent the amount of 3 beta-hydroxyandrost-5-ene-17 beta-carboxylic acid was increased and its 17 alpha-epimer could be detected. This indicates partial artifactual formation of this C20 acid from 21-hydroxypregnenolone, which is known to be present in human meconium. The amount of the saturated C20 acids was unaffected by the presence of sodium borohydride in the extraction medium, and their native occurence in human meconium was further confirmed by the absence of their 17 alpha-epimers in extracts obtained both with and without borohydride. The probable metabolic origin of C20 acids in the fetal-placental-maternal unit is discussed.

Androstanols↗
PubMed1983

Glucose absorption by in vitro perfused colon of the fetal rat.

The anatomic configuration of fetal rat colon resembles that of the small bowel. Accordingly, glucose and amino acid absorption were measured in order to see whether the fetal rat colon resembled the small bowel functionally. In vitro luminal perfusion of the fetal rat colon at 20 days of gestation was employed to measure the rate of glucose and L-alanine absorption and the unidirectional flux rates of 3-O-methylglucose (3-O-MG). The colon was mounted between pipettes in a heated oxygenated bath and perfused with the solute to be studied dissolved in buffered physiological solution and polyethylene glycol with average molecular weight of 4,000 (PEG) as a nonabsorbable marker substance. The PEG was not transported and did not diffuse across fetal colon. Scanning and transmission electron microscopy of perfused and control colon showed the presence of villi and the preservation of mucosal anatomy during perfusion. Glucose was absorbed at 173 +/- 16 mumol . h-1 . g-1 (8) and absorption was abolished in Na-free solution. 3-O-MG flux was 40 +/- 7 mumol . h-1 . g-1 (8) from lumen to bath and 7 +/- 1 mumol . h-1 . g-1 (8) from bath to lumen. L-Alanine flux was 130 +/- 15 mumol . h-1 . g-1 (8) from lumen to bath and 18 +/- 4 mumol . h-1 . g-1 (5) from bath to lumen, and the lumen-to-bath flux was only partially abolished by Na-free solutions.

Alanine↗
PubMed1983

Development of the bile acid pool in rats from neonatal life through puberty to maturity.

The bile acid pools of developing rats were measured by gas-liquid chromatography. From shortly after birth the bile acid pools fell to a nadir on the 10th day of life (0.295 +/- 0.031 mg X g-1 body weight at 2 days to 0.144 +/- 0.012 mg X g-1 body weight at 10 days, p less than 0.001). The pool re-expanded rapidly between the 12th and 15th day. After weaning and during puberty there was a further temporary increase in pool size, during which females had larger pools than males. By adulthood the pool size had returned to the 2-day-old and weanling (15- and 18-day-old) levels, expressed per gramme body weight, and there was no longer a significant sex difference. These results show that changes in pool size are occurring at times when there are major physiological changes in the developing animal. The changes during puberty suggest hormonal control.

Aging↗
PubMed1983

Hepatic metabolism of 3 alpha-hydroxy-5 beta-etianic acid (3 alpha-hydroxy-5 beta-androstan-17 beta-carboxylic acid) in the adult rat.

Normal human meconium has been shown to contain short-chain (C20-C22) bile acids and, recently, these compounds have been identified in sera of patients with cholestasis. This suggests that shortchain bile acids may be secreted in bile. We have examined this point by studying the hepatic metabolism and biliary secretion of one naturally occurring C20 bile acid, 3 alpha-hydroxy-5 beta-etianic acid (3 alpha-hydroxy-5 beta-androstan-17 beta-carboxylic acid). [3-3H]-3 alpha-hydroxy-5 beta-etianic acid was prepared and administered intravenously to rats prepared with an external biliary fistula. 85.5 +/- 1.2% of the administered dose was recovered in bile over 20 h with 71.5 +/- 1.3% appearing in the first hour. 11.9 +/- 1.6% of the dose was estimated to be distributed in body water and 0.6 +/- 0.2% was recovered as organic matter in urine. Total recovery of label was 98.0 +/- 2.6%. Administration of milligram quantities of 3 alpha-hydroxy-5 beta-etianic acid produced an increase in bile flow (58.9 +/- 7.1% over basal levels) within 20 min after injection of the steroid. The radiolabeled material in bile was shown by thin-layer chromatography (TLC) to be a polar conjugate which, after beta-glucuronidase hydrolysis, cochromatographed with authentic free 3 alpha-hydroxy-5 beta-etianic acid. After purification, and derivatization, the steroid moiety was proven by gas chromatography-mass spectrometry to be identical to 3 alpha-hydroxy-5 beta-etianic acid. Characterization of the conjugate by TLC and by 3 alpha-hydroxysteroid dehydrogenase assay, before and after beta-glucuronidase hydrolysis, indicated that the steroid was secreted in bile as the 3-O-beta-glucuronide. It is concluded that 3 alpha-hydroxy-5 beta-etianic acid is cleared from the plasma, conjugated with glucuronic acid, and secreted into bile rapidly and in high concentration. The choleretic properties of this shortchain bile acid contrast with the cholestatic effects of lithocholic acid, its C24 analog. Both the form of conjugation of etianic acid and its effect on bile flow suggest that the shortened side chain of this steroid markedly alters its hepatic metabolism and physiology.

Androstanols↗
PubMed1983

Diversity of bile acids in the fetus and newborn infant.

The bile acids found in the fetus and newborn are more numerous and diverse than has generally been appreciated. The four conventional bile acids, cholic, chenodeoxycholic, deoxycholic, and lithocholic acids, are found. In addition, however, stereoisomers of the conventional bile acids, bile acids with functional groups at different positions or in greater number than found in conventional bile acids, and "short-chain" and "long-chain" bile acids are found. The site of origin, pathways of synthesis, metabolism, and excretory routes of these unconventional bile acids are largely unknown. Their effects on the function of the liver and other tissues have not yet been established. It is uncertain which of these compounds is peculiar to the fetus and newborn, and which will be found in normal or abnormal adults. This review is an early look at a field bound to advance rapidly in the next several years.

Bile↗
PubMed1983

Pregnancy-related changes in small intestinal myoelectric activity in the rat.

To determine if changes in intestinal motility occur during pregnancy, we studied small intestinal myoelectric activity, using monopolar electrodes, in fasted pregnant rats from day 12 to day 18 of the 22-day gestation period. We also studied fasting myoelectric activity in postpartum, nonpregnant, and castrate females. In all rats, the interdigestive myoelectric complex was invariably present with recurring activity fronts appearing at the proximal electrode and moving slowly abroad. Intervals between fronts were similar in all four groups, ranging from 12.61 min to 14.58 min. In pregnant rats, however, there was loss of the periodicity characteristic of activity fronts in the other groups; intervals up to 43 min in length were occasionally noted. Unorganized, randomly occurring spike potentials characterized these intervals. The average coefficient of variation of interval length was significantly (p less than 0.05) greater in pregnant rats (0.401) than in castrate (0.197) and nonpregnant rats (0.248). These studies confirm the presence in rats of pregnancy-related changes in small intestinal myoelectric activity.

Animals↗
PubMed1982

Glucagon stimulation of hepatic Na+, K+-ATPase.

In the perfused rat liver administration of glucagon was shown to result in a transiently increased uptake of K+, indicating the possible involvement of the Na+, K+-ATPase. Direct measurement of the activity of Na+, K+-ATPase revealed a two-fold stimulation of the enzyme by glucagon. The effect of glucagon on the activity of the enzyme was immediate. Simultaneously with the increase in the activity of the Na+, K+-ATPase, the activity of Mg2+-ATPase decreased. In order to evaluate whether the activation of the Na+, K+-ATPase by glucagon is related to the metabolic effects of the hormone, experimental conditions known to interfere with the activity of the enzyme were employed and glucagon stimulation of Ca2+-efflux, mitochondrial metabolism and gluconeogenesis were measured. K+-free perfusate, high K+ perfusate or ouabain interfered to varying degrees with the glucagon stimulation of these responses. The combination of K+-free perfusate and ouabain almost completely abolished the glucagon stimulation of all three parameters. These results demonstrate the glucagon stimulation of Na+, K+-ATPase and raise the possibility that the activation of the enzyme by glucagon might be a necessary link for the manifestation of its metabolic effects.

Animals↗
PubMed1982

Effect of pregnancy on gastrointestinal transit.

In order to evaluate the possible effects of pregnancy-associated sex steroids on gastrointestinal function, we determined gastrointestinal transit times and sex steroid levels in 15 women during the third trimester of their pregnancies and again 4--6 weeks following delivery when gastrointestinal function had symptomatically returned to normal. Gastrointestinal transit time from ingestion of a liquid lactulose meal to its delivery to the cecum was determined by monitoring breath hydrogen concentrations at 10-min intervals. Gastrointestinal transit times were significantly prolonged in the third trimester of pregnancy, when progesterone and estradiol levels were increased, compared to the postpartum period. This study supports previous findings which suggest that increasing levels of progesterone and estradiol affect gastrointestinal function and therefore may contribute to gastrointestinal symptoms that often occur in pregnant women.

Adult↗
PubMed1982

Constituents of human meconium: II. Identification of steroidal acids with 21 and 22 carbon atoms.

Monohydroxylated acid fraction isolated from human meconium was found to contain, in addition to C20 and C24 acids identified previously, three C22 bile acids-(20S)-3 alpha-hydroxy-23,24-bisnor-5 beta-cholan-22-oic, (20S)- and (20R)-3 beta-hydroxy-23,24-bisnor-chol-5-en-22-oic, and one C21 acid-3 beta-hydroxypregn-5-en-21-oic. These compounds were identified by capillary gas chromatography-mass spectrometry and by comparison with standards. It is postulated that these C22 acids, as well as the two monohydroxylated C24 bile acids (lithocholic and 3 beta-hydroxychol-5-enoic) are produced in the maternal intestine by microbial flora and transferred to the fetus through the placenta.

Bile Acids and Salts↗