Biomedical subjects

A F Hofmann

Publications and source records attributed to A F Hofmann.

At least 289 records · Page 16Linked to original sources

PubMed1975

Metabolism of [35S]taurine in man.

Taurine metabolism in man was defined by an isotope dilution technique during normal taurine intake (five subjects) or increased taurine intake (two subjects). A tracer dose of [35S]taurine was administered intravenously, and the amount and chemical form of radioactivity were determined in blood, urine, bile, and feces. Analysis of plasma specific activity decay curves indicated that taurine metabolism can be described by two exchangeable pools: a small (2 mmoles), rapidly exchanging pool (t1/2 approximately equal to 0.1 hour); and a large (98 mmoles), very slowly exchanging pool (t1/2 approximately equal to 70 hours). A small amount of [35S]isethionic acid was detected in urine, possibly the result of deamination of taurine by tissues; but otherwise no evidence of tissue biotransformation was obtained. Taurine was excreted predominantly (95%) in urine, about 70% as taurine and 25% as sulfate. The sulfate was considered to be formed in the intestine by bacterial degradation of taurine and then absorbed. Supplemental taurine (given orally) was well absorbed, caused a transient increase in plasma taurine levels, was excreted in urine without equilibration with the slowly exchangeable pool, and caused only a modest increase in total body taurine. Thus, taurine resembles other amino acids in having large tissue pools but differs strikingly in being metabolically inert with an extremely slow turnover rate.

Adult↗

PubMed1975

Biliary lipid output during three meals and an overnight fast. I. Relationship to bile acid pool size and cholesterol saturation of bile in gallstone and control subjects.

Using a duodenal perfusion technique, the biliary output of bile acids, phospholipid, and cholesterol was measured hourly during three meals and an overnight fast in seven Caucasians with radiolucent gallstones in a functioning gallbladder, and in seven health controls without gallstones, closely matched for age, sex, and weight. Before the perfusion, bile acid kinetics were defined by an isotope dilution procedure, and the biliary lipid composition of fasting gallbladder bile was determined. Total daily biliary lipid output was similar in gallstone and control subjects, and was unrelated to cholesterol saturation of fasting gallbladder bile and to bile acid pool size. There was an inverse relationship between the size and recycling frequency of the bile acid pool, so that secretion rate and hepatic return of bile acids remained constant, despite a wide range of pool sizes. The finding of a normal bile acid synthesis rate in subjects with a small pool size therefore indicated normal feedback regulation of bile acid synthesis. Hourly measurements of biliary lipid output showed a linear relationship between bile acid and cholesterol output, with a similar regression line for gallstone and control subjects, but a non-linear relationship between bile acid and phospholipid output. Consequently, samples from all subjects were consistently supersaturated with cholesterol at low bile acid outputs, especially during overnight fasting, but not at high bile acid outputs. These findings indicate that hepatic secretion of bile supersaturated with cholesterol is physiological in man at low bile acid outputs, that bile acid pool size is probably determined in part by its recycling frequency, and that cholesterol cholelithiasis in some Caucasians may be due to an underlying extrahepatic abnormality.

Adult↗

PubMed1975

Biliary lipid output during three meals and an overnight fast. II. Effect of chenodeoxycholic acid treatment in gallstone subjects.

Oral treatment with chenodeoxycholic acid causes dissolution of cholesterol gallstones in man. In order to determine the mechanism of this effect, we have measured 24-hour biliary lipid output, lipid composition of fasting gallbladder bile, and bile acid pool sizes before and during such treatment in six patients with radiolucent gallstones in functioning gallbladders. In all six patients, the degree of cholesterol saturation of fasting-state gallbladder bile was decreased during treatment to a level below the thermodynamic solubility line. This effect was due to a decrease in biliary cholesterol output, associated with conversion of more than 90% of the total bile acid pool to chenodeoxycholic acid. It could not be attributed to an increase in total bile acid pool size nor to an increase in biliary bile acid or phospholipid output.

Administration, Oral↗

PubMed1975

Metabolism of lithocholate in healthy man. II. Enterohepatic circulation.

Studies were carried out in healthy subjects to characterize the enterohepatic circulation of lithocholate and its metabolites. When mixed with bile and infused into the jejunum, radiolabeled lithocholylglycine was absorbed more rapidly and more efficiently than sulfolithocholylglycine, based on recovery from bile. When these metabolites were administered at 1800 hr in a liquid test meal containing radiolabeled taurocholate as an absorbable marker, 60% of lithocholylglycine was conserved, based on recovery of radioactivity in fasting bile the following morning, but only 20% of sulfolithocholylglycine was conserved. Iotope dilution studies in 4 subjects showed that daily input of lithocholate into the bile acid pool averaged 100 mg per day, about one-third to one-half of the chenodeoxycholic acid synthesis, but the t 1/2 was extremely short (0.74 day). The small lithocholate pool (about 100 mg) could be explained by rapid fecal excretion caused by sulfation which decreases passive absorption in the jejunum and active absorption in the ileum. Experiments with [35S]sulfo- [3H]lithocholylglycine indicated little desulfation during enterohepatic cycling but rapid desulfation in the distal intestine, with absorption of 35S (presumably as sulfate) followed by urinary excretion. A decreasing 35S:3H ratio in bile indicated that some steroid moiety was conserved to be resulfated. These studies indicate that considerable lithocholate is absorbed from the distal intestine in healthy subjects but efficient sulfation results in rapid fecal excretion, so that the total lithocholate pool remains small. A multicompartment model, previously used to describe the metabolism of the steroid and amino acid moieties of the major conjugated biliary bile acids, was extended to encompass lithocholyl conjugates and their sulfates.

Chenodeoxycholic Acid↗

PubMed1975

Validation of use of 11,12-2H-labeled chenodeoxycholic acid in isotope dilution measurements of bile acid kinetics in man.

Chenodeoxycholic acid labeled with 2H in the 11 and positions was prepared by catalytic reduction of delta 11-12 unsaturated derivatives of cholic acid. To validate the use of this stable isotope for the determination of bile acid kinetics by isotope dilution, it was administered to seven normal male volunteers simultaneously with [24-14C]chenodeoxycholic acid. Bile was collected at regular intervals over the following 5 days, and the chenodeoxycholic acid pool size and fractional turnover rate were determined from the specific activity decay curve for 14C and from the isotopic abundance curve for 2H. Estimates of the pool size by both isotopes showed a correlation of r = 0.95 and similar precision. Synthesis rate, the product of pool size and fractional turnover rate, also showed good agreement (r = 0.97), Because previous investigations have shown that bile acids tagged with hydrogen isotopes at the 11 and 12 positions are stable in man, the present data suggest that 11, 12-2H-labeled bile acids may be used in place of radioactive isotopes for valid isotopic measurement of bile acid kinetics in healthy infants and children.

Adult↗

PubMed1975

Influence of primary bile acid feeding on cholesterol metabolism and hepatic function in the rhesus monkey.

In three healthy rhesus monkeys fed chenodeoxycholic (chenic) acid, there was no consistent increase in the total exchangeable cholesterol pool or input to the cholesterol pool. In three similar monkeys fed cholic acid, the total exchangeable pool increased in all animals and input to the cholesterol pool increased in two. Serum glutamic-pyruvic transaminase (SGPT) increased transiently in two animals in each group. Morphologic abnormalities (triaditis with atypical ductular proliferation) were noted in one animal; this animal was ingesting chenic acid but had normal liver test results at the time of biopsy. Biliary bile acids contained 8 to 14 percent lithocholic acid in the chenic acid group and 48 to 72 percent deoxycholic acid in the cholic acid group.

Alanine Transaminase↗

PubMed1975

Thin-layer chromatographic separation of sulfated and nonsulfated lithocholic acids and their glycine and taurine conjugates.

A method for superior thin-layer chromatographic separation of lithocholic acid and its N-glycine and N-taurine conjugates, as well as their respective 3alpha-sulfates, is described. A solvent system of chloroform-methanol-acetic acid-water 65:24:15:9 (v/v) is used with air-dried plates of silicic acid containing calcium sulfate (10% by weight) under conditions of chamber saturation.

Cholic Acids↗

PubMed1975

Biliary bile acid composition in Wilson's disease.

Biliary bile acid composition and pattern of bile acid conjugation with glycine or taurine were found to be within normal limits in six patients with documented Wilson's disease. Four patients had previous biopsy evidence of cirrhosis (three with active hepatitis), but most conventional liver function tests gave normal results at the time of the study. Serum levels of conjugates of cholic acid, measured by radioimmunoassay, were not increased. However, plasma disappearance if intravenously injected glycine conjugate of cholic acid was significantly delayed in all subjects, suggesting that this is a more sensitive test of hepatic excretory function and may be of value for assessing hepatic function in patients with this rare genetic disorder. No evidence of a primary disturbance in bile acid metabolism was found in these patients.

Adolescent↗

PubMed1975

Plasma disappearance of radioactivity after intravenous injection of labeled bile acids in man.

The kinetics of disappearance of radioactivity from plasma after intravenous injection of radiolabeled bile acids was characterized in healthy subjects. Cholic and chenodeoxycholic acids and their N-glycine and N-taurine conjugates were studied along with the secondary bile acid, deoxycholic acid, and a synthetic conjugated bile acid, dehydrocholyltaurine. Disappearance of each primary bile acid was rapid and could be described by a biexponential curve (t 1/2 the first component, 1.7 to 3 min; second component, 7 to 16 min). Cholyglycine and cholyltaurine had identical disappearance rates which were significantly faster than the disappearance rates of chenodeoxycholylglycine and chenodeoxycholyltaurine, which were also identical. Radioactivity of a conjugated bile acid disappeared more rapidly than that of its unconjugated form, but all of these differences, although consistent, were small. Deoxycholic acid radioactivity disappeared slightly more slowly than that of the primary bile acids. In vitro, dihydroxy bile acids were bound by serum proteins more completely (96 to 98%) than trihydroxy bile acids (83 to 91%), whether free or conjugated, and binding was unrelated to bile acid concentration. Thus, plasma disappearance rates were related to the degree of protein binding to some degree in that those bile acids which were more tightly bound had the longer t 1/2 values. However, dehydrocholyltaurine showed little protein binding (42%), yet had the slowest disappearance rates; t 1/2 values averaged 4 and 36 min for the two components of the disappearance curve. The results suggest that the residence time of any bile acid in blood is extremely short, and that measurable concentrations of serum bile acids persist only because of continuous intestinal absorption. It is speculated that the reported difference between the pattern of fasting state serum bile acids and biliary bile acids is explained by differences in intestinal absorption and hepatic uptake of individual bile acids.

Adult↗

PubMed1975

Metabolism of lethocholate in healthy man. I. Biotransformation and biliary excretion of intravenously administered lithocholate, lithocholylglycine, and their sulfates.

The metabolism of intravenously injected radiolabeled lithocholate, lithocholylglycine, and their 3alpha-sulfate esters was characterized in healthy subjects. Lithocholate radioactivity was excreted rapidly and predominantly in bile; the excreted radioactivity had the chromatographic properties of glycine and taurine conjugates of lithocholate, of which 60% were sulfated. Lithocholylglycine also was excreted rapidly and predominantly in bile, and 60% of excreted radioacitvity was sulfated. Sulfolithocholate radioactivity was only partially conjugated (about 60%) in association with biliary excretion. Sulfolithocholylglycine was excreted unchanged in bile. Neither sulfated derivative showed appreciable excretion in urine, although both were excreted more slowly in bile than unsulfated free or conjugated lithocholate. The data suggest that unconjugated lithocholate which is absorbed is completely conjugated and partially sulfated before excretion which occurs exclusively in bile. Since sulfation is not complete, some unsulfated lithocholate is always present in bile. This conjugated but unsulfated lithocholate, if reabsorbed, would be again partially sulfated during its next enterohepatic circulation. Thus, the end result of these biotransformations would be for absorbed lithocholate to be excreted in bile mostly, but not entirely as the sulfated conjugates.

Bile↗

PubMed1975

Metabolism of lithocholate in healthy man. III. Plasma disappearance of radioactivity after intravenous injection of labeled lithocholate and its derivatives.

The plasma disappearance of intravenously injected radiolabeled lithocholate, lithocholylglycine, and their respective 3alpha-sulfates was defined in healthy subjects. Binding of these bile acids to serum protein in vitro was measured by ultrafiltration. Lithocholate and lithocholylglycine rapidly disappeared from plasma (t1/2 less than 3 min), showing a behavior similar to that of the other major primary bile acids present in man. However, after 15 min, when 99% of the radioactivity had been cleared, the disappearance curve flattened, and chromatography suggested that the chemical form of circulating radioactivity had become sulfolithocholylglycine, the end product of hepatic metabolism of lithocholate in man. Injected sulfolithocholate and sulfolithocholylglycine were cleared about one-fourth as rapidly. Lithocholate and its derivatives were tightly bound to serum proteins (87 to 99%); for a given steroid moiety and mode of conjugation, binding was altered slightly by sulfation, but all sulfated derivatives were tightly bound (greater than 95%) to serum protein. The results indicate that lithocholate, which enters the plasma compartment, whether unconjugated, conjugated, or conjugated and sulfated, will be protein-bound but nonetheless will be rapidly cleared from plasma.

Adult↗

PubMed1975

Effect of primary bile acid ingestion on bile acid metabolism and biliary lipid secretion in gallstone patients.

Bile acid kinetics were measured by isotope dilution, and hourly outputs of bile acid, cholesterol, and phospholipid were quantified by duodenal perfusion over 24 hr including three liquid meals and an overnight fast in 6 gallstone patients during a pretreatment period and two randomized treatment periods with chenodeoxycholic (chenic) acid or cholic acid. During chenic acid ingestion, bile contained predominantly chenyl conjugates. During cholic acid ingestion, bile was composed of about equal amounts of cholyl and deoxycholyl conjugates; chenyl conjugates decreased markedly due in part to a 50% decrease in chenic acid synthesis. Total bile acid pool size doubled in half the patients receiving either bile acid and was not different during treatment with chenic or cholic acid. Compared to cholic acid, chenic acid caused decreased cholesterol output with no difference in bile acid or phospholipid output. Therefore, bile unsaturated with cholesterol entered the duodenum for more hours per day during chenic acid ingestion than during the cholic or pretreatment periods. There was no relationship among bile acid pool size, bile acid output, and hours per day of supersaturated bile; there was an inverse relationship between total pool size and recycling frequency such that bile acid output remained stable over a wide range of pool sizes. Fasting-state gallbladder bile was supersaturated during the cholic and pretreatment periods, but became unsaturated during chenic acid ingestion. However, hours per day of supersaturated bile could not be reliably predicted from the degree of saturation of fasting-state gallbladder bile (r = 0.62). The efficacy of chenic acid and the lack of efficacy of cholic acid for gallstone dissolution appear related to their different specific effects on biliary cholesterol secretion and not to any effect on bile acid and phospholipid secretion or bile acid pool size.

Bile↗

PubMed1975

Fasting serum bile acid levels in the primary hyperlipoproteinemias.

A newly developed radioimmunoassay specific for conjugates of cholic acid (CCA) was used to measure the fasting serum levels of these bile acids in 233 patients with primary hyperlipoproteinemia classified as type IIa, IIb, III, IV, or V hyperlipoproteinemia as well as in 80 healthy control subjects. Subjects with type IIa hyperlipoproteinemia had significantly lower levels of CCA (0.9 plus or minus 0.06 muM, mean plus or minus SE) than did healthy controls (0.50 plus or minus 0.08 muM). Patients with type IIb, III, IV, and V hyperlipoproteinemia had values similar to those of the control group. The abnormally low fasting value of CCA in type IIa patients is considered to reflect decreased secretion of bile acid into the intestine in such patients, who are known to have defective bile acid synthesis rates and decreased bile acid pool sizes.

Adult↗

PubMed1974