Influence of taurocholate on hepatic clearance and biliary excretion of asialo intestinal alkaline phosphatase in the rat in vivo and in isolated perfused rat liver

Rüssel, Frans G. M.; Weitering, J.G.; Oosting, Roelof; Groothuis, Geny M. M.; Hardonk, M. J.; Meijer, Dirk K. F.

doi:10.1016/0016-5085(83)90304-9

Cited by 17 publications

(7 citation statements)

References 36 publications

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“…As the efflux process remains operational during more than 90 min, it seems highly improbable that this is due to release from a plasma membrane-bound pool. The concept of diacytosis of endocytosed ligands is rapidly gaining acceptance from observations with a diversity of proteins such as dog intestinal alkaline phosphatase (43), horseradish peroxidase (44), polymeric IgA (45), lactoferrin (46), human asialotransferrin (47) and ASOR (48).…”

Section: Discussionmentioning

confidence: 99%

Drug targeting to the liver with lactosylated albumins: Does the glycoprotein target the drug or is the drug targeting the glycoprotein?

et al. 1986

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The isolated perfused rat liver preparation was employed to study hepatic disposition of the model drug-carrier conjugate fluorescein-lactosylated albumin (F-LnHSA) with special reference to the influence of the organic anion fluorescein on liver cell specificity of the endocytosed neoglycoprotein. Hepatic clearance of fluoresceinated neoglycoproteins was significantly faster than clearance of radioiodinated neoglycoproteins. Perfusate clearance of F-L7HSA and F-L25HSA could not completely be inhibited by a dose of 10 mg asialoorosomucoid that saturates the hepatocyte receptor-mediated endocytic process. From these data, we inferred an additional hepatic uptake mechanism, competing with the Ashwell-receptor-mediated internalization of galactose-terminated glycoproteins. Clearance experiments with fluoresceinated 125I-human serum albumin in the presence of the polyanionic probe dextran sulfate revealed a nearly complete (approximately 90%) inhibition of hepatic uptake, while also a pronounced effect was obtained with colloidal carbon. These data point to nonparenchymal cell uptake of fluoresceinated protein via interaction with scavenger receptors. In wash-out studies, it was shown that about 25% of ligand sequestrated by sinusoidal liver cells escaped degradation and recycled to the perfusion medium. Our results show that care should be taken in the use of neoglycoproteins as drug carriers to hepatocytes, since a load of only 2 to 3 moles fluorescein per mole neoglycoprotein considerably affects intrahepatic distribution. The relative contribution of nonparenchymal cell uptake by coupling of acidic drugs to the neoglycoproteins is very probably inversely related to the number of exposing galactose groups per molecule neoglycoprotein. This phenomenon of "inversed targeting" could therapeutically both be useful or detrimental, dependent on the spectrum of cell types that should be reached by the drug.

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Section: Discussionmentioning

confidence: 99%

Drug targeting to the liver with lactosylated albumins: Does the glycoprotein target the drug or is the drug targeting the glycoprotein?

et al. 1986

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“…The biliary secretion of a small percentage of intact ASOR has been described, and attributed to ligand missorting [19]. The delivery of other intact asialoglycoproteins to bile [20,21] as well as a diacytosis pathway that delivers endocytosed ligands back into the circulation intact also have been reported [22,23]. That we found a rather high TCA precipitability of radioactivity released back into the perfusate was surprising, as the release of intact diacytosed molecules reportedly requires Ca2 + chelation [24] ; the perfusion medium used in our expeirments contained physiologic levels of Ca2+.…”

Section: Discussionmentioning

confidence: 99%

Effects of monensin on vesicular transport pathways in the perfused rat liver

Kloppel

Brown

Reichen

1986

J of Cellular Biochemistry

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In the rat hepatocyte, the internalization and degradation of asialoglycoproteins and the secretion of plasma and biliary proteins require specific intracellular sorting of vesicles. To aid in the biochemical characterization of these different vesicular pathways, we examined the effects of the ionophore monensin on the uptake and degradation of 125I-asialoorosomucoid (ASOR) and on the secretion of plasma and biliary proteins by the in situ perfused rat liver. In control livers, 77% of injected 125I-ASOR was extracted on first pass; 93% of the extracted radioactivity was released back into the circulation (totally degraded and some intact ASOR was found); and approximately 2% was recovered in the bile, some of which was intact. Monensin treatment decreased first pass uptake of 125I-ASOR to 57% and abruptly blocked the release of radioactivity into the perfusate and the bile. When hepatic proteins were biosynthetically labeled with 3H-leucine, monensin treatment dramatically reduced and delayed the secretion of newly synthesized proteins into both the perfusate and the bile. In contrast with control livers, in which secretion of protein into the perfusate preceded secretion of protein into the bile, TCA-precipitable 3H-protein appeared in bile about 20 min before TCA-precipitable 3H-protein appeared in the perfusate in monensin-treated livers. Thus, monensin treatment in the perfused liver blocked the degradation of asialoglycoproteins and inhibited the secretion of plasma proteins but had less effect on biliary protein secretion. These data document physiologic effects of monensin in an intact organ and suggest that biochemical distinctions between different vesicular pathways exist in the rat hepatocyte.

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“…The liver asialoglycoprotein receptor is responsible for the clearance of APs from the circulation . The AP intestinal isoform cleared by the liver asialoglycoprotein receptor is secreted in bile .…”

Section: Aps and Lapmentioning

confidence: 99%

Liver alkaline phosphatase: A missing link between choleresis and biliary inflammation

Poupon

2015

Hepatology

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Several lines of evidence show that serum alkaline phosphatase (AP) is not only a signpost of cholestasis but also a surrogate marker of the severity of primary biliary cirrhosis and primary sclerosing cholangitis. In the present opinion article, we review and discuss the putative role of liver AP in health and in cholestatic diseases. In inflammatory cholestatic conditions, loss of activity of liver AP (resulting from its relocation from canaliculi and the acidic milieu) might promote hyper‐adenosine triphosphate‐bilia, lipopolysaccharide overload, and subsequent exacerbation and perpetuation of inflammation. Drugs that can restore the polarity of hepatocytes and canalicular export of bile acids or act as bile alkalinity modifiers are predicted to exert anti‐inflammatory effects and to benefit both primary biliary cirrhosis and primary sclerosing cholangitis. Oral administration of intestinal AP could be a valid therapeutic intervention that deserves further study under experimental conditions as well as in human diseases. Overall, the key role of the liver microenvironment that might shape the different facets of the inflammatory processes in fibrosing cholangiopathies is highlighted. (Hepatology 2015;61:2080–2090)

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Influence of taurocholate on hepatic clearance and biliary excretion of asialo intestinal alkaline phosphatase in the rat in vivo and in isolated perfused rat liver

Cited by 17 publications

References 36 publications

Drug targeting to the liver with lactosylated albumins: Does the glycoprotein target the drug or is the drug targeting the glycoprotein?

Drug targeting to the liver with lactosylated albumins: Does the glycoprotein target the drug or is the drug targeting the glycoprotein?

Effects of monensin on vesicular transport pathways in the perfused rat liver

Liver alkaline phosphatase: A missing link between choleresis and biliary inflammation

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