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Biomedical subjects

A F Hofmann

Publications and source records attributed to A F Hofmann.

At least 181 records · Page 10Linked to original sources
PubMed1984

Physiologic determinants of biliary calcium secretion in the dog.

Studies were carried out to define the origins and physiologic determinants of biliary calcium secretion in the dog. Canalicular bile flow was varied by infusions of several bile acids or a canalicular choleretic agent, SC2644. Three natural bile acids (cholyltaurine, chenodeoxycholyltaurine, and ursodeoxycholyltaurine) that have a low critical micellar concentration and a synthetic hydroxy-oxo bile acid (12-dehydrocholyltaurine) with a much higher critical micellar concentration were used. Calcium output, bile acid output, and bile flow were determined; canalicular bile flow was assessed by measurement of erythritol clearance. Calcium output increased linearly with bile acid output for all three natural bile acids (r = 0.94; 0.026-0.035 mumol delta calcium/mumol delta bile acid), but chenodeoxycholyltaurine and ursodeoxycholyltaurine infusions induced a slightly greater secretion of calcium for a given bile acid output and bile flow than cholyltaurine. Calcium output also increased linearly with bile flow, whether bile flow was induced by the canalicular choleretic SC2644 (r = 0.93; 0.0018 mumol delta calcium/microliter delta water) or the hydroxy-oxo bile acid (r = 0.99; 0.0021 mumol delta calcium/microliter delta water). Because the calcium output induced by the three micelle-forming bile acids was greater than that which could be explained by the induced increase in bile flow per se, it was deduced that canalicular calcium has two origins: a micellar component that is dependent on the presence of micelles or micelle-forming bile acids and an osmotic component that is dependent on osmotic forces, e.g., caused by secretion induced by SC2644 or bile acid molecules and possibly bile acid micelles. A small bile acid-independent output of calcium was also detected and should contribute to the osmotic fraction. To determine whether ductular modification of bile flow influenced biliary calcium secretion, ductular secretion was induced by secretin and ductular absorption was induced by somatostatin. Changes in calcium output followed water movements, increasing with ductular secretion and decreasing with ductular absorption. The relationship between changes in ductular bile flow and calcium output was identical during induced ductular secretion (r = 0.83; 0.0016 mumol delta calcium/microliter delta water) or induced ductular absorption (r = 0.91; 0.0019 mumol delta calcium/microliter delta water). Thus calcium movements in relation to water movements were identical for the osmotic component of canalicular bile and the ductular component of bile.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Biliary secretion and hepatic metabolism of taurine-conjugated 7 alpha-hydroxy and 7 beta-hydroxy bile acids in the dog. Defective hepatic transport and bile hyposecretion.

Experiments were carried out using chronic bile fistula dogs to define the physiologic properties and metabolism of two unnatural epimeric monohydroxy conjugated bile acids, 7 alpha-hydroxy cholanoyltaurine and 7 beta-hydroxy cholanoyltaurine. The compounds, labeled with 14C, were infused intravenously at a rate of 1 mumol/kg X min; effects on bile flow and biliary lipid secretion as well as hepatic biotransformation were defined. The 7-monohydroxy bile acids were secreted quite slowly in bile: recovery during the 90-min infusion interval averaged 16% for the 7 alpha compound and 23% for the 7 beta compound, and after 6 h was only about 60% for the 7 alpha compound and 80% for the 7 beta compound. Uptake by tissues, presumably the liver, appeared to be efficient, as the level of radioactivity in peripheral blood remained quite low. Both bile acids failed to induce the anticipated increase in bile flow; canalicular bile flow, which was assessed using erythritol clearance, was about half the value observed when cholyltaurine was infused at a similar rate. The "hyposecretion" of bile, which was thought likely to be caused by impaired canalicular transport of the monohydroxy conjugates, was fully reversible, as a subsequent cholyltaurine infusion at a rate of 1 mumol/min X kg immediately restored bile flow and the infused cholyltaurine was secreted normally. Each compound was partly 3-hydroxylated during hepatic passage: the 7 alpha compound, about 36% (to form chenodeoxycholyltaurine); the 7 beta compound, about 23% (to form ursodeoxycholyltaurine). No other biotransformation occurred. Each compound induced phospholipid and cholesterol secretion, but compared to the effects of cholyltaurine, the amount of phospholipid secretion induced (per micromole of secreted bile acid) was less, and that of cholesterol, greater. Thus, the two 7-monohydroxy taurine-conjugated bile acids caused a striking dissociation of induced phospholipid and cholesterol secretion. The results indicate that taurine-conjugated 7-monohydroxy bile acids are poorly secreted by the liver and that their impaired transport is associated with bile hyposecretion, possibly reflecting decreased bile acid-dependent flow; the configuration of their 7-hydroxy group influences their rate of secretion into bile. The results also establish a novel type of bile acid biotransformation (3-hydroxylation) in the dog.

Animals↗
PubMed1983

The influence of bile salt structure on self-association in aqueous solutions.

The relationship between chemical structure and the concentration at which self-association occurs in water or in 0.15 M Na+ ion was examined for more than 50 bile salts and bile salt analogues varying in substituents on the steroid nucleus or in the structure of the side chain. Nuclear substituents varied in type (alpha- or beta-hydroxy, or oxo group) and number (1, 2, or 3); side chain structure varied in the nature of the ionic group (unconjugated, glycine- or taurine-conjugated, or zwitterion) or length of the side chain (5-, 4-, or 3-carbon atoms). The midpoint of the concentration range over which aggregation occurred was called the critical micellar concentration (CMC), even though bile salt aggregation is known to be more gradual than that of most typical ionic detergents. CMC values were obtained by surface tension measurements using an improved maximum bubble-pressure method, as well as by dye solubilization. Results obtained by the two methods agreed well. The CMC values varied from about 1 to greater than 250 mM. For a given bile salt, the addition of a hydroxy or oxo group increased the CMC; and for a given number of substituents, the changing of a hydroxy group to an oxo group increased the CMC values as well. The orientation of hydroxy substituents also influenced the CMC values: the changing of a hydroxy substituent from an alpha- to a beta-configuration increased the CMC values, as bile salts possessing alpha- and beta-hydroxy substituents had higher CMC values than bile salts with only alpha-hydroxy substituents. Inspection of space-filling models suggested the hypothesis that the greater contiguous hydrophobic area of the molecule, the lower the CMC value. The CMC value also increased exponentially as the side chain was shortened from C5 to C4 to C3. Conjugation of the side chain carboxylic group with glycine or taurine, although increasing the length of the side chain, caused little change in the CMC values. The addition of Na+ ion to a total concentration of 0.15 M lowered the CMC in a predictable manner for all anionic bile salts. The results indicate that the concentration at which bile salt aggregation occurs varies widely and is determined not only by the number, type, and orientation of nuclear substituents, but also by side chain structure.

Bile Acids and Salts↗
PubMed1983

Tauroursodeoxycholic acid is less damaging than taurochenodeoxycholic acid to the gastric and esophageal mucosa.

Bile acids are capable of disrupting the gastric and esophageal mucosal barriers and are known to differ in their ability to injure these mucosae. Two bile acids, chenodeoxycholic and its 7-B epimer, ursodeoxycholic, that are being used to dissolve gallbladder stones were evaluated for their damaging effects on experimental preparations of the esophageal (rabbit) and gastric (dog) mucosa. Damage was assessed by measuring indices of mucosal barrier function, including net acid flux, potential difference, and tissue resistance, before and after exposure to the taurine conjugates of these bile acids. In both the esophageal and gastric mucosa, tauroursodeoxycholic acid caused significantly less disruption of barrier function than taurochenodeoxycholic acid. These results demonstrate that minor differences in conjugated bile acid structure can cause major changes in the effects of bile acids on the upper gastrointestinal mucosa and that ursodeoxycholic acid may be the preferred bile acid for oral ingestion to dissolve gallbladder stones.

Animals↗
PubMed1983

A bioluminescent assay for 12-alpha-hydroxy bile acids using immobilized enzymes.

A bioluminescent assay for 12-alpha-hydroxy bile acids was developed using enzymes coimmobilized onto Sepharose 4B. The immobilized enzymes used were a bacterial 12-alpha-hydroxysteroid dehydrogenase, bacterial luciferase, and NADPH:FMN oxidoreductase or bacterial diaphorase. The assay was specific for 12-alpha-hydroxy bile acids and the lower limit of detection was 4 pmol/0.5 ml assay volume with a linear range of 4 to 2000 pmol. Intraassay precision was from 7.8 to 8.2%. Values obtained with this assay showed good agreement with those obtained by gas-liquid chromatography. The system using diaphorase was not stable at 4 degrees C in the absence of added thiol compounds, but could be stabilized by the addition of glutathione (0.5 mM). The assay is a convenient, a rapid, and an extremely sensitive method for the measurement of 12-alpha-hydroxy bile acid concentrations in the serum of patients or experimental animals.

Bile Acids and Salts↗
PubMed1983

Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

A multicompartmental pharmacokinetic model based on physiological principles, experimental data, and the standard mathematical principles of compartmental analysis has been constructed that fully describes the metabolism and enterohepatic cycling in man of cholic acid, a major bile acid. The model features compartments and linear transfer coefficients. The compartments are aggregated into nine spaces based on physiological considerations (liver, gallbladder, bile ducts, jejunum, ileum, colon, portal blood sinusoidal blood, and general circulation). The transfer coefficients are also categorized according to function: flow, i.e., emptying of gallbladder or intestinal spaces, and circulation of the blood; biotransformation, i.e., conjugation, deconjugation, or dehydroxylation; and transport, i.e., active or passive transport. The model is made time dependent by introducing meals, which trigger discrete increases in gallbladder emptying and intestinal flow. Each space contains three compartments. For cholic acid, these are unconjugated cholic acid, cholylglycine, and cholyltaurine. The model was then used with all existing experimental data to simulate cholic acid metabolism in healthy man over a 24-h period. Satisfactory agreement was obtained between simulated and experimental results for serum bile acid levels, hepatic bile acid secretion, and bile acid secretion into the intestine. The model was also used to classify 16 clinical instances in which the enterohepatic circulation of bile acids is altered by drugs or disease. The model can be extended to describe completely the metabolism and enterohepatic circulation of any bile acids in man in health and digestive disease. The model should also be broadly applicable to the description of the pharmacokinetics of all other drugs whose metabolism is similar to that of bile acids, i.e., drugs for which there are tissue and bacterial biotransformations, enterohepatic cycling, and appreciable first-pass clearance.

Bile Acids and Salts↗
PubMed1983

Assay of urinary oxalate: six methodologies compared.

To assess how well results by different methods for urinary oxalate determinations agree with each other in a clinical setting, we compared six different assays: Hodgkinson and Williams (Clin Chim Acta 36:127-132, 1972), enzymatic, modified Hodgkinson and Williams, gas chromatography, ion chromatography, and "high-pressure" liquid chromatography. For the entire group of samples, the mean value by each method agreed relatively closely, although the enzymatic procedure produced a somewhat higher value. All six methods had large coefficients of variation within (8-58%) and between (15-88%) assays. In addition, analytical recovery by most assays was more than 100% of the added oxalate. Analytical recovery of 10 micrograms of oxalate added per milliliter of urine specimen ranged from 86 to 237%; for 20 micrograms/mL it was 83 to 320%. Thus for the six methods evaluated, no single method appeared to be superior to the others.

Chromatography, Gas↗
PubMed1983

Complex pathogenesis of hyperoxaluria after jejunoileal bypass surgery. Oxalogenic substances in diet contribute to urinary oxalate.

Balance studies and oxalate loading tests were carried out in order to define the pathogenesis of hyperoxaluria in 8 patients with jejunoileal bypass surgery for severe obesity; two healthy volunteers were also studied. In the bypass patients, urinary oxalate was markedly elevated (118 +/- 43 mg/day, mean +/- SD) when they were on a high oxalate diet (252 mg/day). Hyperabsorption of dietary oxalate was confirmed by the markedly increased urinary recovery of [14C]oxalate given in a test meal. In addition, the oxalate radioactivity was excreted in urine far more slowly than in healthy volunteers, suggesting that the colon was a major site of oxalate absorption. Elevated urinary oxalate excretion persisted, averaging 38 +/- 12 mg/day, despite ingestion of a very low oxalate diet (approximately 6 mg/day), suggesting that the diet contained "oxalogenic" substances other than preformed dietary oxalate which also contributed to dietary oxalate in these patients. Urinary oxalate decreased in 7 of 8 patients, however, when protein-rich foods were removed from the diet, suggesting that at least one dietary factor was digestive products of protein or creatinine. These results confirm the current view that in patients with hyperoxaluria secondary to jejunoileal bypass, the majority of urinary oxalate derives from dietary oxalate that is absorbed from the colon. Tissue or bacterial production of oxalate or an oxalate precursor from dietary constituents associated with protein, however, also appears to contribute to urinary oxalate. The results provide an explanation for the reported difficulty of eliminating secondary hyperoxaluria by restriction of dietary oxalate alone.

Adult↗
PubMed1982

Differing effects of ursodeoxycholic or chenodeoxycholic acid on biliary cholesterol saturation and bile acid metabolism in man. A dose-response study.

A dose-response study comparing ursodeoxycholic and chenodeoxycholic acid was carried out in six men with asymptomatic radiolucent gallstones present in well-visualizing gallbladders. The study tested the effects of a low (averaging 6 mg/kg/day) or medium dose (averaging 11 mg/kg/day) of each bile acid on the cholesterol saturation of bile as well as on bile acid metabolism, as inferred from biliary and fecal bile acid composition. Ursodeoxycholic acid, at low or medium doses, induced bile desaturation in most patients, whereas chenodeoxycholic acid did not. Despite the greater desaturation efficacy of ursodeoxycholic acid, biliary bile acids became less enriched with the administered bile acid during ursodeoxycholic acid treatment than during chenodeoxycholic acid treatment. Both bile acids were nearly completely 7-dehydroxylated to lithocholic acid by colonic bacteria, but biliary lithocholic increased only slightly (and similarly) with each bile acid. Fecal bile acid composition suggested that administered ursodeoxycholic acid suppressed endogenous bile acid synthesis much less than chenodeoxycholic acid. The results indicate that ursodeoxycholic acid and chenodeoxycholic acid have similar but not identical effects on bile acid metabolism, but that for a given dose, ursodeoxycholic acid is a more potent desaturating agent than chenodeoxycholic acid. The results suggest that cholesterol gallstone dissolution with ursodeoxycholic acid should occur with a dose of 8-10 mg/kg in most nonobese patients.

Aged↗
PubMed1982

Effects of individual taurine-conjugated bile acids on biliary lipid secretion and sucrose clearance in the unanesthetized dog.

The effect of three taurine-conjugated bile acids on bile flow, induced biliary secretion of phospholipids and cholesterol, and the hepatobiliary clearance from plasma of sucrose and erythritol (two uncharged, nonmetabolizable permeability probe molecules) was assessed in the unanesthetized bile fistula dog under steady-state conditions. Synthetically prepared chenodeoxycholyltaurine, cholytaurine, or urological rate for randomized 90-min periods, and four 10-min samples of bile were taken at the end of each period. Induced bile flow (per mumoles of bile acid) was calculated to be about one-third higher with ursodeoxycholyltaurine than with the other bile acids. Induced phospholipid secretion was identical for all bile acids, but cholesterol secretion differed: the two dihydroxy taurine conjugates induced considerably more cholesterol per molecule bile acid or phospholipid than colyltaurine. Further, ursodeoxycholyltaurine induced significantly more cholesterol secretion than chenodeoxycholyltaurine. Erythritol clearances were identical for all bile acids, and sucrose clearance, although slightly higher for chenodeoxycholyltaurine than ursodeoxycholyltaurine, was similar for all three conjugated bile acids. The results indicate that, for these two 3,7-dihydroxy bile acids, the orientation of the 7-hydroxyl group on the steroid nucleus has a marked influence on cholesterol secretion into bile and bile flow but not on the apparent permeability of the hepatobiliary tree.

Animals↗
PubMed1982

Cholecystokinin cholecystography, sonography, and scintigraphy: detection of chronic acalculous cholecystitis.

Because the efficacy of cholecystokinin cholecystography in the detection of chronic acalculous cholecystitis remains in doubt, the procedure is rarely used in clinical practice. However, the ability to observe gallbladder contraction with sonography and 99mTc-para-isopropylacetanilido-iminodiacetic acid cholescintigraphy (PIPIDA) offers a possibility to improve the sensitivity of the test. To determine if the degree of gallbladder contraction after cholecystokinin is the same as measured by the three techniques and if it differs in symptomatic patients compared to the normal population, cholecystokinin cholecystography, cholecystokinin sonography, and cholecystokinin PIPIDA were performed in 10 symptomatic patients and 10 normal volunteers. The mean maximum contraction of the gallbladder during the three studies was 63%, 61%, and 68%, respectively, for the volunteers, and 72%, 63%, and 73%, respectively, for the patients. The mean maximum gallbladder contraction during all three procedures was 64% +/- 26% SD in the volunteers and 74% +/- 17% SD in the patients. The differences were not statistically significant. Although there was good correlation in the degree of maximum gallbladder contraction among cholecystokinin cholecystography, cholecystokinin sonography, and cholecystokinin PIPIDA, marked variation in both the volunteers and the patients makes it unlikely that the degree of contraction as observed by any of these techniques can be used to indicate the presence of chronic acalculous cholecystitis.

Biliary Dyskinesia↗