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Biomedical subjects

A F Hofmann

Publications and source records attributed to A F Hofmann.

At least 361 records · Page 20Linked to original sources
PubMed1970

Synthesis and metabolism of glycerol-3H triether, a nonabsorbable oil-phase marker for lipid absorption studies.

A saturated mixed-chain glycerol triether, 1-hexadecyl-2,3-didodecyl glycerol (1-hexadecoxy-2,3-didodecoxypropane), was synthesized with (3)H at positions 9 and 10 or (14)C at position 1 of the hexadecyl moiety. In acute feeding experiments in rats, less than 0.2% of the triether was absorbed, based on lymph and fecal recoveries. Radioactivity was present exclusively as triether in feces, indicating that it was not degraded by digestive or bacterial enzymes. Chronic feeding experiments in rats confirmed the nonabsorbability of the triether and further indicated that it was nontoxic, did not influence the absorption of dietary fat, and mixed intimately with the fat present in colonic contents and feces. The triether that was absorbed was deposited as triether in adipose tissue, liver, and spleen. When administered intraperitoneally to mice, the triether was stored in the tissues and was not metabolized. When the triether was partitioned between an oil phase of triolein or fatty acid and monoglyceride, and an aqueous micellar phase, the triether remained exclusively in the oil phase. The triether appears to be an ideal nonabsorbable oil-phase marker for use in lipid absorption studies.

Adipose Tissue↗
PubMed1970

Use of 3H-labeled triether, a nonabsorbable oil-phase marker, to estimate fat absorption in rats with cholestyramine-induced steatorrhea.

A tritium-labeled glycerol triether was tested as a nonabsorbable oil-phase marker in studies of fat absorption in normal rats and in rats with steatorrhea induced by various doses of cholestyramine. Animals were fed a test meal containing (3)H-labeled triether and (14)C-labeled trilinolein. Fat absorption was estimated in the following three ways: (a) by isotope ratios (the change in (3)H/(14)C in the test meal and in feces); (b) by isotope recovery (the total fecal excretion of (14)C radioactivity); and (c) by chemical recovery (the total fecal fat excretion). Absorption calculated from isotope ratios agreed well with that calculated from isotope recovery over a range of fat absorption of 50-100%, thus validating the use of this lipid marker under these conditions of fat malabsorption. Absorption calculated from chemical recovery was consistently poorer than that calculated from isotope ratios or isotope recovery, thus suggesting that cholestyramine increased the excretion of nondietary (endogenous) fat. Triether may be of value for studying the absorption of compounds present predominantly in the oil phase during digestion and may have significant advantages over other proposed lipid markers.

Carbon Isotopes↗
PubMed1968

Experimental cholelithiasis in the rabbit induced by cholestanol feeding: effect of neomycin treatment on bile composition and gallstone formation.

Fed cholestanol is converted by the rabbit to 5alpha-bile acids which coprecipitate with the normally occurring 5beta-bile acids to form gallstones composed of calcium and sodium glycoallodeoxycholate and glycodeoxycholate. The present study shows that oral administration of large doses of neomycin prevents gallstone formation in the cholestanol-fed rabbit and reduces the elevated concentration of allodeoxycholic acid in bile, with a reciprocal increase in allocholic acid concentration. The reduction in the concentration of allodeoxycholic acid and in the incidence of gallstones is proportional to the dose of neomycin; at a concentration of allodeoxycholic acid below about 20% of total bile acids, gallstone formation does not occur. Neomycin probably exerts its action by modifying the anerobic intestinal flora which dehydroxylate allocholic acid to allodeoxycholic acid; if so, this suggests that both hepatic and bacterial transformations are essential steps in the pathogenesis of cholestanol-induced cholelithiasis. The bile of rabbits on a normal diet contains allodeoxycholic acid (5% of total bile acids). A similar decrease in allodeoxycholic acid concentration and reciprocal increase in allocholic acid concentration is observed when neomycin is administered to rabbits on a normal diet.

Animals↗
PubMed1968

Rapid preparation of tritium-labeled bile acids by enolic exchange on basic alumina containing tritiated water.

When a 3-keto bile acid methyl ester was chromatographed on basic alumina inactivated with tritiated water, the enolic hydrogen atoms at C-2 and C-4 exchanged with tritium atoms. The (3)H-labeled keto ester was reduced with borohydride, and the resultant mixture of 3alpha- and 3-hydroxy epimers was resolved by preparative thin-layer chromatography to yield a pure 2,4-(3)H-labeled bile acid ester. Lithocholic, chenodeoxycholic, deoxycholic, and cholic acids having a specific activity of 1-10 micro c/ micromole were prepared from their 3-keto derivatives. The tritium label remained intact during alkaline saponification in vitro and enterohepatic cycling in vivo in human subjects.

Aluminum↗
PubMed1967

Absorption of cholesterol from a micellar solution: intestinal perfusion studies in man.

The absorption of cholesterol has been studied in man by perfusing the upper jejunum with a micellar solution of bile salt, 1-monoglyceride, and cholesterol-(14)C, with a triple lumen tube with collection sites 50 cm apart. The absorption of micellar components between the collection sites was calculated from their concentration changes relative to those of the watersoluble marker, polyethylene glycol. Control experiments were performed with cholesterol-free perfusions of saline or bile salt-monoglyceride solutions. Steady state conditions were obtained.Each of the components of the micelle was absorbed to a different extent during passage through the test segment of jejunum. Bile salt was not absorbed (mean, -3%), but micellar monoglyceride was rapidly hydrolyzed and absorbed almost completely (mean, 98%). Cholesterol radioactivity was absorbed to an intermediate extent (mean, 73%), and the absorption of chemically determined cholesterol (mean, 46%) indicated that much of the disappearance of radioactivity represented true absorption and not simple exchange. The specific activity of the perfused cholesterol fell during passage through the loop. This fall was interpreted as signifying the continuous addition of nonradioactive endogenous cholesterol by the test segment. However, the decrease in specific activity may also be considered to signify exchange, in that nonradioactive molecules entered the lumen as radioactive molecules were absorbed. Plant sterols appeared in the intestinal contents during the perfusion and must have been contributed by the perfused segment. The perfusate and samples taken from the upper and lower collection sites were examined by ultracentrifugation to define the physical state of cholesterol. It was found that cholesterol in the perfusate or upper collection site samples did not sediment, but that 23% of the cholesterol in the lower collection site samples was sedimentable (mean of three experiments); bile salt, as control, was not sedimentable. Solubility experiments in model systems showed that cholesterol possessed low solubility in bile salt solution; its solubility increased markedly and in linear proportion to the amount of fatty acid or monoglyceride or both that was added to the bile salt solution. These findings suggest that polar lipid such as fatty acid or monoglyceride as well as bile salt is essential for normal micellar solubilization of cholesterol in intestinal content. They suggest the necessity of considering an insoluble sedimentable phase of particulate sterol in intestinal content as well as an oil and micellar phase for a complete description of sterol absorption. The marked difference in the rates of absorption of individual micellar components suggests that micellar lipid is not absorbed as an intact aggregate and is consistent with the view that polar lipid such as fatty acid is absorbed in molecular form by diffusion from a micellar solution. The experiments confirm previous findings demonstrating that fat absorption without bile salt absorption occurs in the upper small intestine in man.

Adult↗
PubMedDate not supplied

The continuing importance of bile acids in liver and intestinal disease.

Bile acids, the water-soluble, amphipathic end products of cholesterol metabolism, are involved in liver, biliary, and intestinal disease. Formed in the liver, bile acids are absorbed actively from the small intestine, with each molecule undergoing multiple enterohepatic circulations before being excreted. After their synthesis from cholesterol, bile acids are conjugated with glycine or taurine, a process that makes them impermeable to cell membranes and permits high concentrations to persist in bile and intestinal content. The relation between the chemical structure and the multiple physiological functions of bile acids is reviewed. Bile acids induce biliary lipid secretion and solubilize cholesterol in bile, promoting its elimination. In the small intestine, bile acids solubilize dietary lipids promoting their absorption. Bile acids are cytotoxic when present in abnormally high concentrations. This may occur intracellularly, as occurs in the hepatocyte in cholestasis, or extracellularly, as occurs in the colon in patients with bile acid malabsorption. Disturbances in bile acid metabolism can be caused by (1) defective biosynthesis from cholesterol or defective conjugation, (2) defective membrane transport in the hepatocyte or ileal enterocyte, (3) defective transport between organs or biliary diversion, and (4) increased bacterial degradation during enterohepatic cycling. Bile acid therapy involves bile acid replacement in deficiency states or bile acid displacement by ursodeoxycholic acid, a noncytotoxic bile acid. In cholestatic liver disease, administration of ursodeoxycholic acid decreases hepatocyte injury by retained bile acids, improving liver tests, and slowing disease progression. Bile acid malabsorption may lead to high concentrations of bile acids in the colon and impaired colonic mucosal function; bile acid sequestrants provide symptomatic benefit for diarrhea. A knowledge of bile acid physiology and the perturbations of bile acid metabolism in liver and digestive disease should be useful for the internist.

Bile↗