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Biomedical subjects

R F Hanson

Publications and source records attributed to R F Hanson.

At least 37 records · Page 2Linked to original sources
PubMed1979

Hepatic extraction of bile salts in conscious dogs.

The enterohepatic circulation of cholic acid conjugates (CAC) was studied in three conscious dogs by comparing the relationship of the concentration of CAC in portal, hepatic, and peripheral venous plasma samples collected simultaneously. The pool of CAC in each dog was labeled with 14C. Catheters were surgically placed in the jugular, left hepatic, and portal veins. Each dog was studied on 2 consecutive days, and each study consisted of a series of samples withdrawn from each catheter at 15-min intervals before and after gallbladder contraction with cholecystokinin. The concentration of CAC in the portal vein ranged from 3 micron (fasting) to 235 micron (after gallbladder contraction). In individual studies, the concentration of CAC increased four to sixfold. A linear relationship exists between the concentration of CAC in the portal vein to that in the hepatic and jugular veins. Thus, the fractional hepatic extraction of CAC is constant over the physiological range of the concentration of CAC in portal venous plasma. Mean extraction varied among the six studies from 0.618 +/- 0.072 (+/- 1 SD) to 0.983 +/- 0.010.

Animals↗
PubMed1979

Metabolism of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 26-tetrol and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol into cholic acid in normal human subjects.

Side chain oxidation and cleavage of precursors in cholic acid synthesis is thought to involve initial hydroxylation at either position 25 or 26 of the side chain. Therefore, the conversion of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 26-tetrol and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol into cholic acid was studied in normal subjects after single intravenous injections of these labeled alcohols. Eighty-six percent and 82% of 5 beta-cholestane, 3 alpha, 7 alpha, 12 alpha, 26-tetrol was converted into cholic acid in two subjects, respectively. However, only 14 and 16% of the injected 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol was converted into cholic acid in two subjects, respectively. Thus, this study indicates that 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol is an inefficient substrate for cholic acid biosynthesis in man and that the major route of cholic acid synthesis probably involves the 26-hydroxylated intermediate.

Carbon Radioisotopes↗
PubMed1979

Micellar properties of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oyl taurine and relationship to in vitro red cell disruption.

Patients with a metabolic block in the conversion of THCA to cholic acid develop cirrhosis and hemolysis. Tauro-THCA has been shown to distort hepatic architecture and cause hemolysis in bile-fistula rats. In this study, the critical micellular concentration of tauro-THCA was found to be one fourth of that measured for the primary human bile salt, taurocholate. In short-term incubations with intact red cells, tauro-THCA was more effective than taurocholate in removing red cell membrane lipid, inducing morphological red cell sphering, and decreasing functional cellular membrane surface area. These detergent biological membrane effects were most apparent at a concentration above the critical micellar concentration, with the membrane toxicity of the two bile salts roughly paralleling their differences in critical micellar concentration. The lower critical micellar concentration, greater hydrophobicity, and enhanced surface-active properties of tauro-THCA are speculated on as possible factors contributing to the bile salt's toxicity in vivo.

Animals↗
PubMed1979

Bile acid metabolism in the cirrhotic rat.

Bile acid metabolism was studied in rats with cirrhosis induced by carbon tetrachloride (CCl4). Although the typical histologic features of cirrhosis were seen, cholestasis was not present in these animals as evidenced by a normal total serum bilirubin concentration and by a normal hepatic capacity to remove taurocholate infused intravenously. The cirrhotic rats also secreted taurocholate into bile at a normal rate. The total bile salt pool size in the cirrhotic rats was not significantly different from the pool size in normal rats (10.59 +/- 1.19 mumoles per gm. of liver (+/- 1 standard error of the mean) and 10.43 +/- 0.92 mumoles per gm. of liver, respectively). When the bile was drained externally through a chronic bile fistula, the normal rats increased the bile salt synthetic rate approximately 3-fold after 48 hours of drainage. However, the cirrhotic rats failed to significantly increase the synthetic rate for bile salts in response to biliary drainage. The normal rats also had a significant increase in cholic acid synthesis at the maximal synthetic rate, whereas the cirrhotic rats did not. These findings indicate that (when feedback inhibition is removed) CCl4 cirrhotic rats lack the ability to normally increase the activity of 7 alpha-hydroxylase and 12 alpha-hydroxylase, rate-limiting enzymes in the synthesis of bile salts.

Animals↗
PubMed1978

Effect of taurocholate on the conversion of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid into cholic acid.

To determine if the conversion of the intermediate, 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid (THCA), into cholic acid is influenced by taurocholate, two rats were infused intravenously with [3H] THCA until they reached a steady state. Taurocholate was then added and infused at a rate of 1 mumole/min/rat for 48 hours. The percentage of [3H] THCA recovered in the bile did not increase indicating that taurocholate does not suppress the conversion of THCA into cholic acid.

Animals↗
PubMed1977

Hepatic lesions and hemolysis following administration of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oyl taurine to rats.

Patients with a metabolic block in the conversion of THCA into cholic acid develop cirrhosis and hemolysis, and die of hepatic failure. In these patients, THCA is largely conjugated to taurine (tauro-THCA) and excreted instead of being converted into cholic acid. In the present study, the effects of tauro-THCA on hemolysis, bile flow, and hepatic morphology were evaluated in bile fistula rats. All rats infused with tauro-THCA at rates of 0.25, 0.50 or 0.75 micronmol/min developed hemolysis with hemoglobinuria. A direct toxic effect of tauro-THCA on washed human red blood cell membranes was demonstrated at a concentration of 8 X 10(-4) M. Liver biopsy sections from rats infused for a 2 hr period with tauro-THCA were examined by electron microscopy and showed dilation of the rough endoplasmic reticulum and distortion of mitochondrial membranes. Cholestasis was not induced, since tauro-THCA actually caused a greater choleretic response for a given rate of bile salt excretion than did taurocholate. This study raises the possibility that the clinical liver disease seen in patients with a metabolic block in the conversion of THCA into cholic acid may be caused by tauro-THCA.

Anemia, Hemolytic↗
PubMed1977

Metabolism of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid in normal subjects with an intact enterohepatic circulation.

The formation of cholic acid from 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid (THCA) was studied in two normal subjects. [3H]THCA and [14C]cholic acid were administered intravenously by simultaneous injection and the specific activities (percent injected amount/mumol) of [3H]- and [14C]cholic acid were measured in bile samples collected over a 5-day period. If the administered [3H]-THCA is rapidly and completely metabolized into cholic acid, the areas under the specific activity curves of [3H]- and [14C]cholic acid should be identical. In these two subjects, the area under the [3H]cholic acid specific activity decay curves was only 18.4% and 9.0% less than the area under the [14C]cholic acid specific activity decay curves. Thus, there is rapid and nearly complete metabolism of intravenously administered [3H]THCA into cholic acid.

Adult↗
PubMed1976

Evidence for carrier proteins in bile acid synthesis. The effect of squalene and sterol carrier protein and albumin on the activity of 12alpha-hydroxylase.

The possibility that carrier proteins are involved in bile acid synthesis was investigated using rat liver homogenates. The 105 000 X g supernatant fraction was found to contain heat stable proteins that bound the bile acid precursor, 7alpha-hydroxy-4-cholesten-3-one, and increased the amount of 7alpha, 12alpha-dihydroxy-4-cholesten-3-one formed by the microsomal enzyme, 12alpha-hydroxylase. Subsequent studies were carried out to determine if squalene and sterol carrier protein or albumin, two lipid binding proteins present in the 105 00 X g supernatant fraction of rat liver homogenates, may be responsible for the effects seen with this fraction. Squalene and sterol carrier protein bound several water insoluble bile acid precursors, including 7alpha-hydroxy-4-cholesten-3-one, and increased the apparent activity of 12alpha-hydroxylase. Squalene and sterol carrier protein, however, did not bind either cholic acid or chenodeoxycholic acid. Rat serum albumin also bound 7alpha-hydroxy-4-cholesten-3-one and increased the apparent activity of 12alpha-hydroxylase. Kinetic analysis indicated that the apparent stimulation of 12alpha-hydroxylase by squalene and sterol carrier protein and albumin was due to increased solubilization of the substrate, 7alpha-hydroxy-4-cholesten-3-one. Thus, these studies indicate that bile acid precursor carrier proteins are present in the 105 000 Xg supernatant fraction of rat liver homogenates and suggest that squalene and sterol carrier protein or albumin may participate as carrier proteins in bile acid synthesis.

Animals↗
PubMed1976

Formation of bile acids in man. Metabolism of 7alpha-hydroxy-4-cholesten-3-one in normal subjects with an intact enterohepatic circulation.

The formation of bile acids in man is thought to involve a series of reactions in which the initial steps are the same for both cholic acid and chenodeoxycholic acid. The point of bifurcation of the pathway is postulated to occur after the formation of 7alpha-hydroxy-4-cholesten-3-one. To test the hypothesis that the entire synthesis of both bile acids proceeds through this intermediate we studied the metabolism of labeled 7alpha-hydroxy-4-cholesten-3-one in eight normal subjects with an intact enterohepatic circulation. If all the production of cholic acid and chenodeoxycholic acid takes place via 7alpha-hydroxy-4-cholesten-3-one, the areas under the specific decay curves of cholic acid and chenodeoxycholic acid should be identical following a single injection of this labeled intermediate. However, in 6 of the 8 subjects studied the area under the cholic acid specific activity decay curve was significantly less than the area under the chenodeoxycholic acid specific activity decay curve. These results that the production of cholic acid in man may not always involve the intermediate 7alpha-hydroxy-4-cholesten-3-one.

Adult↗
PubMed1976

Jaundice associated with polycystic liver disease. Relief by surgical decompression of the cysts.

Jaundice is an unusual feature of polycystic liver disease. In a 46-year-old woman with polycystic liver disease and jaundice, the bilirubin level was 42.0 mg/100 ml. Because of the rapid rise in bilirubin level, relief of supposed obstruction of intrahepatic bile ducts was attempted by unroofing the hepatic cysts. Following operation the bilirubin level returned to normal, and the patient has remained well since.

Bilirubin↗
PubMed1976

Immunodeficiency, xanthomas and obstructive liver disease.

Chronic obstructive liver disease and secondary hyperlipidemia developed in an immunodeficient boy. Sequential addition of cholestyramine and phenobarbital to his medical regimen, following an initial response to bile drainage, resulted in the disappearance of xanthomas and pruritus, and the restoration of normal serum concentrations of lipids and bile acids. This improvement may result from shifting the bile acid pool from the peripheral blood compartment to the enterohepatic circulation.

Bile Acids and Salts↗
PubMed1976

The metabolism of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid into cholic: an enzyme assay using homogenates of human liver.

An enzyme assay was developed to measure the conversion of the bile acid precursor, 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid (THCA), into cholic acid using homogenates of human liver biopsies. The average rate of metabolism of THCA into cholic acid was found to be 3.9 +/- 0.5 (+/- 1 SD) pmoles of cholic acid formed/mg liver/minute in twelve normal liver biopsies. This assay system can be used to determine if the syndrome of neonatal cholestasis associated with a metabolic block in the conversion of THCA into cholic acid is transmitted as a genetic trait.

Adolescent↗
PubMed1975

Failure to demonstrate degradation of (4-14C) cholesterol to volatile hydrocarbons in rats and in human fecal homogenates.

The inability of previous workers to recover completely the radioactivity from ingested [4-14C] cholesterol has led to the hypothesis that the colonic flora of some individuals degrade the sterol nucleus to volatile hydrocarbons, particularly CH4. In the present investigation, the production of radioactive volatiles was measured following incubation of [4-14C] cholesterol with 8 human fecal homogenates or after instillation of the labeled sterol into the cecum of 3 rats housed in a closed rebreathing system. Three of the 8 homogenates and each of the 3 rats produced copious CH4. However, analysis by combustion demonstrated no radioactivity above background in the volatile headspace of the homogenates or the gas space of the closed system housing the rats, indicating that less than 0.001% of the number 4 carbon of [4-14C] cholesterol could have been converted to volatile hydrocarbons. This study, therefore, provides no support for the concept that volatile products account for the incomplete recovery of ingested sterols observed in certain subjects. However, this hypothesis can not be excluded entirely until similar results are obtained with subjects who can be shown to degrade cholesterol.

Animals↗
PubMed1975

The metabolism of 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid in two siblings with cholestasis due to intrahepatic bile duct anomalies. An apparent inborn error of cholic acid synthesis.

Studies were carried out in a family in which two children with cholestasis due to intrahepatic bile duct anomalies were shown to have increased amounts of the cholic acid precursor, 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid (THCA). The metabolism of THCA was studied in one of these patients after an intravenous injection of (3H)THCA, and the cause of the increased amounts of THCA in this condition was found to be due to a metabolic defect in the conversion of this compound into cholic acid. A small amount of (3H)cholic acid was also identified after (3H)THCA administration, confirming that this metabolic defect was incomplete. Varanic acid (3alpha, 7alpha, 12alpha, 24xi-tetrahydorxy-5beta-cholestan-26-oic acid), a metabolite of THCA, could not be identified in either of these patients. By assuming that this compound would be conjugated and excreted if the metabolic block occurred after the formation of varanic acid, the defect in these patients appears to be due to a deficiency of a 24-hydroxylating enzyme system required to convert THCA into varanic acid. This condition appears to be transmitted in an autosomal recessive fashion, because the two affected patients were of opposite sex, and neither a normal sibling nor the two parents have increased amount of THCA in their bile.

Adult↗
PubMed1973

Bile acid formation in man: metabolism of 7 -hydroxy-4-cholesten-3-one in bile fistula patients.

7alpha-Hydroxy-4-cholesten-3-one is thought to be an intermediate in human bile acid synthesis. This conclusion is based on in vivo experiments in animals and on in vitro studies in which homogenates of animal and human livers were used. To further establish that this compound is an intermediate in human bile acid synthesis, its metabolism was studied in subjects with complete bile fistulas. After administration of (3)H-labeled 7alpha-hydroxy-4-cholesten-3-one by single intravenous injection, approximately 85% of the administered isotope was recovered in the bile during the first 12 hr. More than 96% of the radioactivity recovered in the bile was identified as either chenodeoxycholic acid or cholic acid, with only a trace amount of the radioactivity present as neutral sterols. This study gives support to the hypothesis that 7alpha-hydroxy-4-cholesten-3-one is a natural intermediate in human bile acid synthesis.

Bile Acids and Salts↗