Biomedical subjects
Publications and source records attributed to D K Meijer.
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In bile specimens from postoperative patients with biliary drainage following cholecystectomy, in addition to unchanged dibromosulfophthalein (DBSP), a single polar metabolite of DBSP was found after i.v. injection of 5 mg/kg of the diagnostic dye. This metabolite, which has not previously been detected, was resistant to beta-glucuronidase and arylsulfatase and was remarkably stable in strongly acid and alkaline solutions. It exhibited the same spectrum and colour change interval as unchanged DBSP. Further studies of its identity revealed that it gave a ninhydrin-positive reaction and that its Rf-value on TLC could be restored by Raney-nickel reduction. Amino-acid analysis after reduction and acid hydrolysis showed an increase in glutamic acid and alanine that can be considered as splitting products of conjugated glutathione following these procedures. Estimation of the quantity of this possible glutathione conjugate indicates that it is formed less rapidly than the glutathione derivative of the tetrabromoanalogue BSP, and that it represents up to 25% of the total dye excreted in bile. The observed metabolism of DBSP in man may complicate its use in the study of hepatic transport function, and negates the previous assumption that, as in certain other animal species, the dye is excreted unchanged.
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We have used canine intestinal alkaline phosphatase, an asialoglycoprotein, as a tool to study the effect of taurocholate on hepatic asialoglycoprotein transport. After bolus injections of 20 U of alkaline phosphatase into anesthetized rats in vivo and isolated perfused rat livers, a biexponential disappearance pattern was observed; 6.2% of the dose and 0.8% of the dose was excreted in bile, respectively. Taurocholate infusion in vivo and in isolated perfused livers resulted in a virtually complete abolition of the plasma disappearance of alkaline phosphatase in the second slow phase of the curve, whereas the primary disappearance rate was not affected. Wash out experiments showed release of exogenous alkaline phosphatase from the liver, which was strongly increased by taurocholate. Liver perfusion experiments with two subsequent doses of alkaline phosphatase indicated that the taurocholate effect was completely reversible. It is concluded that taurocholate enhances exocytosis of interiorized alkaline phosphatase from liver into plasma. The taurocholate effect on hepatic exocytosis of the asialoglycoprotein may also occur when bile salt concentrations in the systemic or portal circulation, or both, are elevated due to certain liver diseases and postprandial bile salt absorption.
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Glycoproteins represent a wide variety of macromolecules with important physiological functions. Characteristic variations in carbohydrate composition and plasma concentration of these proteins may occur during pathological conditions. Steady-state plasma concentrations are determined by release from normal or diseased tissues and simultaneous clearance from the general circulation. The liver occupies a central position in the production but also clearance and catabolism of such glycoproteins. A number of specialized receptor-mediated transport processes for different types of glycoproteins in this organ is reviewed. Membrane recognition is generally followed by absorptive endocytosis and vesicle transport to lysosomes, Golgi system and/or bile canaliculis. The charge of the protein, the nature of the terminal sugar residue or complex formation with other glycoproteins may determine the extent of uptake in the various cell types of the liver. By means of these transport processes the liver is able to remove potentially dangerous macromolecules such as denatured proteins, aggressive enzymes and immunocomplexes from the general circulation. Drugs can bind to some of these proteins or may interact with the hepatic transport or catabolism processes. Special attention is paid to the hepatic clearance of asialoglycoproteins with terminal galactose groups. Intestinal alkaline phosphatase is used as a model compound to characterize the pharmacokinetic profiles of hepatic uptake and biliary excretion in the rat in vivo and isolated perfused rat livers. Histochemical and electron-microscopic studies demonstrated a galactose-specific, receptor-mediated endocytotic process, mainly but not exclusively localized in centrolobular hepatocytes. Drug interactions with these processes will be the subject of further investigations.
The hepatic transport of three different drugs, the organic anion dibromosulphophthalein, the organic cation d-tubocurarine and the uncharged compound ouabain was studied in vivo in the isolated perfused rat liver and isolated hepatocytes. The respective clearances by uptake were determined for the various substrates and corrected for differences in hepatic blood flow and extracellular protein binding in the three liver preparations. The corrected uptake values in the intact organ, in vivo and in the isolated perfused liver were highly comparable; for dibromosulphophthalein a clearance of 2.1 ml/min per 10(6) hepatocytes was found in vivo, whereas in perfusion a value of 2.4 ml/min per 10(6) cells was calculated. For d-tubocurarine, the values were 34 x 10 (-4) and 55 x 10(-4) ml/min per 10(6) cells obtained in vivo and in the isolated perfused organ, respectively. With ouabain as the substrate, the in vivo clearance amounted to 5.1 x 10(-2), whereas in the isolated perfused liver a value of 4.8 x 10(-2) ml/min per 10(6) cells was calculated. The clearance by uptake obtained for dibromosulphophthalein was ouabain in the isolated hepatocytes appeared to be a factor of 2-3 lower than in the intact organ. In the case of d-tubocurarine however the clearance was identical to that in vivo and the isolated perfused liver. The rate of secretion from isolated hepatocytes was, for dibromosulphophthalein identical to, and for d-tubocurarine and ouabain lower than that in the intact organ, especially as compared with the in vivo preparation. It is concluded that transport function is well preserved in the isolated perfused liver and isolated hepatocytes. For certain substrates freshly isolated hepatocytes may exhibit a somewhat lower uptake and/or secretion rate, in spite of a good cell quality as judged by generally accepted criteria for cell viability. Whether this is due to changes in membrane composition (not detected by our viability tests) or a selection of a subpopulation of hepatocytes, is discussed.U
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This study describes the "plasma" disappearance and biliary excretion of injected purified canine intestinal alkaline phosphatase in the isolated perfused rat liver and in the intact rat. The plasma disappearance curve of the enzyme showed, apart from an initial rapid phase, a secondary phase, which may result from "exocytosis" of interiorized canine intestinal alkaline phosphatase into the circulation or from exhaustion of receptors involved in uptake of the enzyme during the process of endocytosis. A small fraction of the injected enzyme was found to be excreted into the bile and it was shown that there is a "kinetic" relationship between the biliary excretion pattern and the "plasma" disappearance of the enzyme. In addition, the effect of various sugars, sugar polymers and glycoproteins on plasma disappearance and biliary excretion of the enzyme was studied. Intravenous administration of galactose, lactose, galactan and especially asialofetuin prior to injection of canine intestinal alkaline phosphatase, resulted in inhibition of plasma disappearance of the enzyme, while the biliary excretion pattern of the enzyme was also changed. It is concluded that the rapid removal of injected canine intestinal alkaline phosphatase is predominantly, or even exclusively, achieved by the liver and that the hepatic uptake of the enzyme is most likely mediated by the "galactose-specific lectin" present on the plasma membrane of the hepatocytes.
After intravenous administration to rats, the distribution of injected canine intestinal alkaline phosphatase in the liver was studied morphologically by means of histochemical and cytochemical methods on liver sections and pellets of homogenized livers. The interference of various sugars, sugar polymers and glycoproteins with the receptor-bound injected enzyme was investigated in rat liver sections. Injected canine intestinal alkaline phosphatase, being an asialoglycoprotein, is captured by the galactose-specific lectin present on the plasma membrane of the hepatocytes and can be displaced by incubation with galactose-containing sugars and proteins. The enzyme is subsequently taken up by a process of "adsorptive endocytosis" and was found first in a plasma membrane fraction and later in a pellet enriched in lysosomes. This hepatic handling of the enzyme predominantly occurs in the area around the central vein (zone 3 of Rappaport). This is the first evidence for zonal heterogeneity in hepatic disposition of an asialoglycoprotein.
Uptake of taurocholate into plasma membrane vesicles isolated from rat liver was investigated. In the presence of an extra- to intravesicular gradient of Na+ ions, a typical "overshoot" phenomenon in the accumulation pattern was observed. Osmotic manipulation of the incubation medium indicated that the transport of this bile acid occurs into an osmotically active intravesicular space. Uptake of taurocholate as measured after 1 min was specifically stimulated by Na+ ions: NaNO3 and NaCl were capable of supporting accumulation, whereas KNO3 was not. Na+-coupled uptake of taurocholate showed saturation kinetics and was inhibited by other bile acids or by preloading the vesicles with Na+. Our observations support the idea of a carrier-mediated bile-acid uptake system, as suggested previously for the intact rat liver and isolated rat hepatocytes. When the electrical potential difference across the vesicle membrane was changed by inducing different diffusion potentials (anion replacement), a more negative potential inside stimulated Na+-dependent taurocholate transport. The results demonstrate that rat-liver plasma membrane vesicles possess an electrogenic Na+-coupled transport system for taurocholate.
A combination of autoradiography of water-soluble compounds and normal and retrograde perfusions was used to study whether there was a heterogeneity in bile salt transport between zone 1 and zone 3 hepatocytes of the rat and, if so, whether such a heterogeneity was due to the localization of these cells in the liver blood-stream, to intrinsic cellular differences, or to both. When a low dose of [3H]taurocholate was administered under pentobarbital sodium anesthesia in vivo or to normally perfused livers, the label was localized primarily in zone 1; in livers perfused in a retrograde direction, it appeared predominantly in zone 3. High doses of [3H]taurocholate administered in vivo and in normal and retrograde perfusions resulted in a more homogeneous labeling of the acini. The plasma disappearance of [3H]taurocholate was similar in normal and retrograde perfusions, but in the latter biliary excretion occurred at a considerably slower rate. From these results it is concluded that at low doses bile salts are primarily transported by zone 1 cells. Zone 3 cells appear to be able to take up taurocholate with ease, but their biliary excretion is slower compared with zone 1 cells.
The valepotriates isovaltrate and valtrate, and the essential oil compound valeranone caused a suppression of rhythmic contractions in a closed part of the guinea-pig ileum in-vivo. The same compounds and didrovaltrate relaxed potassium stimulated contractures and inhibited BaCl2 contractions in guinea-pig ileum preparations in-vitro. Guinea-pig stomach fundic strips stimulated by carbachol were also relaxed by these substances. Potassium stimulated smooth muscle cells were also relaxed by the valeriana compounds (10(-5)-10(-4) M) even, when autonomic receptors were blocked by appropriate antagonists. In lower concentrations (10(-6)-10(-5) M), the compounds did not affect the dose-response curves of carbachol and isoprenaline. In some experiments valeranone at 4.10(-6) M produced an increased isoprenaline relaxation of the guinea-pig ileum. Valeranone and didrovaltrate were about equipotent to papaverine in inhibiting BaCl2 contractions. It is concluded that the valeriana compounds probably relax stimulated smooth muscle cells by acting as musculotropic agents and not by interacting with receptors of the autonomic nervous system.
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The transport of a series of charged drugs and other organic ions through lipid bilayers was studied, using single-bilayer liposomes. Monovalent organic cations and organic anions could carry charge into the liposomes independent of the nature of their counter ion. Ion-pair formation, following the addition of an excess of I- or Br-, did not facilitate this transport. However the passage of organic cations and anions across the membrane required the presence of the organic anion tetraphenylborate in the lipid bilayer. This effect of tetraphenylborate is probably due to a lowering of an intra-membrane potential energy hill, the principal barrier for transport, and not to ion-pair formation. It is concluded that organic ions that possess sufficiently lipophilic structures to mask their charged character, can pass lipid bilayers in charged form.
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The neuromuscular blocking effects of Org 6368 and Org NC 45 were studied in rats with experimental cholestasis and in controls. The effect of Org NC 45 during infusion of taurocholate was investigated. In cholestatic rats we observed a three-fold increase of the duration of action of Org 6368 and Org NC 45. The same was observed for Org NC 45 with taurocholate. In the rat phrenic nerve-hemidiaphragm preparation taurocholate potentiated the neuromuscular blockade of Org 6368, pancuronium and gallamine, but not Org NC 45. Increased bile salt concentrations caused strong inhibition of hepatic uptake and biliary excretion of Org 6368 and tubocurarine in isolated perfused livers. Taurocholate and glycocholate were more potent than cholate and chenodeoxycholate. Cholestatic livers exhibited a clearance of Org 6368 which was 50% of control. We conclude that the prolonged duration of action of certain muscle relaxants because of cholestasis results from both inhibition of hepatic uptake by the accumulated bile salts and a general deterioration of liver transport function.