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At least 19 recordsLinked to original sources
PubMed1981

Decrease of a hepatic binding protein specific for asialoglycoproteins with accumulation of serum asialoglycoproteins in galactosamine-treated rats.

Acute liver injury was induced experimentally in rats by a single injection of a large amount of D-galactosamine. Hepatocellular damage was apparent from decrease of total serum proteins, marked release of transaminases into the circulation, precipitous decrease of total microsomal proteins, and intracellular enzymes such as cytochrome P450 and 5'-nucleotidase. In parallel with such hepatocellular damage, serum asialoglycoproteins accumulated markedly, reaching a maximum level 4 days after the injection and then decreased to the control level. In contrast to this increase, hepatic binding protein, a receptor in the liver which specifically recognizes asialoglycoproteins, decreased very much. At the same time, survival time of [125I]asialoorosomucoid intravenously administered into rats was much prolonged in inverse proportion to the decrease of the binding protein. From these results it was concluded that the decrease of the hepatic binding protein induced by galactosamine treatment is probably responsible for the marked accumulation of serum asialoglycoproteins.

Animals↗
PubMed1996

Decreased binding of asialoglycoproteins to hepatocytes from ethanol-fed rats. Consequence of both impaired synthesis and inactivation of the asialoglycoprotein receptor.

Chronic ethanol administration alters the process of receptor-mediated endocytosis in isolated rat hepatocytes. Using the asialoglycoprotein receptor (ASGP-R) as a model, we have previously shown decreased binding of asialoglycoproteins to this receptor after as early as 1 week of ethanol administration. In the present study, we further analyzed the mechanism(s) responsible for this impairment by determining the ligand and antibody binding characteristics of the ASGP-R in rats fed ethanol over a 5-week time course. The results presented here demonstrate that ethanol treatment for 4 days significantly impaired total ligand binding without affecting antibody binding. Ethanol administration for a longer period of 1-2 weeks resulted in intermediate impairments in both ligand and antibody binding. After 5 weeks of ethanol exposure, ligand and antibody binding were equally lowered. In contrast to total cellular receptor binding, surface binding of both ligand and antibody were decreased over the entire time course of ethanol administration. Our data indicate that the ASGP-R is initially inactivated during the time course of ethanol exposure and that a redistribution of surface receptors to intracellular compartments occurs. Northern blot analysis showed that there was a significant decrease in receptor mRNA content in the 5-week chronically fed animals but not in the animals fed for 1 week. In addition, after 5 weeks of ethanol feeding, biosynthetic labeling of the ASGP-R was decreased in the ethanol cells, indicating impaired synthesis of the ASGP-R. In summary, an early inactivation of the ASGP-R occurs during ethanol exposure followed by an actual decrease in protein and mRNA content for the receptor.

Animals↗
PubMed1983

The large intracellular pool of asialoglycoprotein receptors functions during the endocytosis of asialoglycoproteins by isolated rat hepatocytes.

The function of intracellular asialoglycoprotein receptors during the endocytosis of asialo-orosomucoid in isolated hepatocytes was assessed by following changes in the occupancy of intracellular receptors. Unoccupied total cellular (inside and surface) or surface receptors were quantified at 0 degrees C by the binding of 125I-asialo-orosomucoid in the presence or absence, respectively, of digitonin. Freshly isolated cells had about 17% of their total receptors on the surface. After incubation at 37 degrees C, the receptor distribution changed to 25 to 50% on the cell surface and 50 to 75% inside the cell. At 37 degrees C, the average total number of receptors/cell was 4.5 x 10(5). Dissociation constants, determined from equilibrium binding studies in the presence or absence of digitonin to assess total or surface receptors, were identical (5.4 +/- 1.4 and 5.6 +/- 1.1 x 10(-9) M, respectively). In the presence of asialo-orosomucoid at 37 degrees C, there was both a time- and a concentration-dependent decrease in surface and intracellular receptor activity. This receptor activity decrease was reversed by removing asialo-orosomucoid from the medium or by washing the digitonin-permeabilized cells with ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid prior to quantification of receptor activity. Within 1 to 2 h in the presence of excess asialo-orosomucoid, a steady state was attained in which approximately 70% of the intracellular receptors were occupied. The kinetics of receptor activity recovery on the cell surface after internalization of a pulse of ligand is different than the rate of recovery of internal receptor activity. The results suggest that all of the internal asialoglycoprotein receptors are functional and participate during endocytosis. Internal receptors may be functionally equivalent to those on the surface or they may serve a reservoir or routing function for internalized ligand.

Animals↗
PubMed1986

Antibody-induced receptor loss. Different fates for asialoglycoproteins and the asialoglycoprotein receptor in HepG2 cells.

The human asialoglycoprotein receptor (ASGP-R) is a membrane glycoprotein which participates in receptor-mediated endocytosis and delivery of its ligands to lysosomes for degradation. In order to examine the pathways and mechanisms responsible for the turnover and degradation of the ASGP-R we have followed the fate of the ASGP-R in HepG2 cells during exposure to anti-receptor antibody as well as inhibitors of lysosomal processing and receptor recycling. Incubation of cells at 37 degrees C with anti-ASGP-R antibody results in the rapid (t 1/2 30 min) loss of mature 46,000-Da ASGP-R (control, t 1/2 20 h). This process requires whole IgG, since Fab fragments do not induce loss of receptor. Furthermore, this antibody-induced loss is specific, since incubation with antibody to the transferrin receptor does not alter cellular ASGP-R content. Of note, weak bases (e.g. primaquine) abrogate this antibody-induced loss of ASGP-R. Inhibitors of lysosomal proteases (EC64 and leupeptin) do not alter this antibody-mediated loss. Furthermore, this effect occurs at 18 degrees C, a temperature at which delivery of ligand to the lysosome is blocked. Thus, the present observations suggest a unique pathway for antibody-induced ASGP-R loss which is distinct from the pathway of lysosomal delivery of ligand.

Antigen-Antibody Complex↗
PubMed1976

Asialoglycoprotein clearance in the chicken: evidence for the lack of a hepatic asialoglycoprotein receptor.

The behaviour of desialylated human and chicken acid alpha1-glycoproteins is reported in chickens. Although desialylation resulted in accelerated disappearance rates from the plasma of both proteins, nevertheless the asialoproteins were eliminated much more slowly than expected on the basis of earlier observations in mammals. Analysis of tissue radioactivities, including kidney, liver, lung and spleen, failed to demonstrate any accumulation of the labeled asialoproteins in the liver, which is contrary to the situation in mammals. The main pathway for the elimination of desialylated human acid alpha1-glycoprotein in the chicken is via the kidney (tubular catabolism and/or urinary excretion). The clearance of desialylated chicken acid alpha1-glycoprotein is more complex as it involves the kidney as well as the reticuloendothelial system. These findings indicate that, unlike mammals, chickens do not possess a hepatic plasma membrane receptor for asialoglycoproteins. This raises the possibility that the presence or absence of this specific receptor may constitute a fundamental biological difference between mammals and birds.

Animals↗
PubMed1991

Trafficking of asialoglycoproteins and the asialoglycoprotein receptor.

Thus, the ASGP-R, a liver parenchymal cell-specific receptor, directs the receptor-mediated endocytosis of galactose-terminal glycoprotein ligands from the circulation into the liver cell, as seen in Figure 3. Following binding at the cell surface and internalization, the major pathway of ligand and receptor movement in the cell involves trafficking to CURL. Here acidification dissociates ligand from receptor, allowing the receptor to recycle back to the cell surface and directing ligand on to lysosomal degradation. Alternative routes of ligand movement, such as the slow ligand-recycling pathway, have recently been observed, and it is tempting to speculate that this occurs by the TGR. There is now ample biochemical, kinetic, and morphological evidence to support both rapid receptor recycling as well as slow receptor recycling associated with ligand recycling. The importance of CURL in the dissociation and segregation of ligand and receptors as well as in receptor recycling and of the recently described TGR are now evident. In addition, the ASGP-R of the hepatocyte has provided interesting parallels and contrasts to other receptor systems that participate in receptor-mediated endocytosis in liver parenchymal cells (155).

Asialoglycoprotein Receptor↗
PubMed1994

Ethanol inhibits asialoglycoprotein receptor synthesis but augments its mRNA expression in a human hepatoma cell line.

The effect of ethanol on the expression of asialoglycoprotein receptor protein and its mRNA was studied in a human hepatoma cell line, HepG2. The number of asialoglycoprotein receptors on the cell surface was decreased to 60% of the control level, without a loss in affinity, by incubating the cells with 100 mM ethanol. The decrease in cell surface asialoglycoprotein receptors was paralleled by a decrease in total receptor numbers, including intracellular and surface receptors. The internalization of asialoglycoprotein was also diminished, to 44% of that in control cells. The decreases in cell surface receptors and total receptor numbers were partially restored by 2 mM 4-methylpyrazole, suggesting that ethanol metabolites participated in the diminution of asialoglycoprotein receptor expression. However, the steady-state expression of asialoglycoprotein receptor mRNA was increased in ethanol-treated cells and further augmented by a longer ethanol exposure. These paradoxical results, i.e., the decrease of asialoglycoprotein receptor protein and the increase of its mRNA expression, suggest that the reduction in the asialoglycoprotein receptor protein is a post-transcriptional event and that a possible feedback regulatory mechanism may control asialoglycoprotein receptor gene transcription and/or impair the degradation of its mRNA.

Alcohol Dehydrogenase↗
PubMed1991

IgG is associated with the asialoglycoprotein receptor in the human liver.

Various pathophysiological relationships between IgA and the asialoglycoprotein receptor on hepatocytes have been proposed. As a step toward defining these relationships, we purified the receptor from human livers by means of p-aminophenyl beta-D-thiogalactopyranoside-agarose affinity chromatography. Unexpectedly, we found the asialoglycoprotein receptor to be associated specifically with IgG. Evidence for the specific association included the following: (a) IgG, but little IgA or IgM, was associated with asialoglycoprotein receptor that had been bound to asialoorosomucoid in an enzyme-linked immunosorbent assay; (b) the asialoglycoprotein receptor-associated IgG was predominantly IgG2 and IgG4 subclasses, whereas serum IgG is predominantly IgG1; and (c) some asialoglycoprotein receptor was specifically recovered together with IgG from an anti-IgG affinity column. The association of IgG with asialoglycoprotein receptor was not mediated by receptor recognition of carbohydrate moieties because IgG neither bound directly to asialoglycoprotein receptor nor inhibited binding of asialoglycoprotein receptor to asialoorosomucoid in vitro. The association could not be attributed to antigen-antibody interaction either. We conclude that IgG is associated in vitro with the asialoglycoprotein receptor by a mechanism not yet fully defined and speculate that the IgG serves an immunological function.

Antibodies, Anti-Idiotypic↗
PubMed1990

Autoantibodies to human asialoglycoprotein receptor in autoimmune-type chronic hepatitis.

Autoantibodies to the human asialoglycoprotein receptor (anti-h-ASGPR) were studied with a solid-phase ELISA in the sera of 421 patients with inflammatory liver diseases, 288 patients with various other disorders and 31 controls. Anti-h-ASGPR were found predominantly in autoimmune chronic active hepatitis (44 of 88, 50%) and were closely related to inflammatory activity. In a subpopulation of these patients with untreated, biopsy-proven active disease or relapse, 15 of 17 were positive (88%). In contrast, only 11 of 204 patients (5.3%) with viral hepatitis were anti-h-ASGPR receptors-positive (chi 2 analysis; p less than 0.001). We also compared the occurrence of anti-h-ASGPR with antibodies to rabbit and rat asialoglycoprotein receptors in 352 sera. In contrast to the anti-human asialoglycoprotein receptor antibodies (3 of 107), anti-rabbit- or anti-rat-asialoglycoprotein receptor antibodies were found in 21 and 28 of 107 cases of viral hepatitis, indicating that different epitopes were recognized by these sera. In various other diseases anti-human asialoglycoprotein receptor antibodies were rarely found. Some sera from patients with connective-tissue diseases (8 of 73) and primary or secondary liver malignancies (6 of 55) exhibited anti-h-ASGPR. In autoimmune chronic active hepatitis the presence of anti-human asialoglycoprotein receptors did not correlate to other established autoantibody systems. Thus we conclude that anti-human asialoglycoprotein receptor antibodies can serve as diagnostic markers for inflammatory active cases of autoimmune chronic active hepatitis. Immune reactions to the asialoglycoprotein receptor, which is expressed on the hepatocellular membrane as a liver-specific antigen, might contribute to the pathogenesis of autoimmune chronic active hepatitis.

Adolescent↗
PubMed1984

Ultrastructural immunocytochemical localization of the asialoglycoprotein receptor in rat hepatocytes.

The asialoglycoprotein receptor is present on the plasma membrane of rat hepatocytes and mediates the endocytosis of exogenous asialoglycoproteins. The intracellular locations of the receptor are incompletely defined, and whether the receptor is present on the canalicular membrane is controversial. To investigate these unresolved issues, we localized the asialoglycoprotein receptor on the surfaces of and within rat hepatocytes in the absence of exogenous asialoglycoprotein. Cryostat sections of perfusion-fixed livers of fasted rats were incubated with peroxidase-labeled antibodies to the rat asialoglycoprotein receptor and were examined by light and electron microscopy. The asialoglycoprotein receptor on the surface of hepatocytes was present on the sinusoidal plasma membrane and was concentrated in coated pits; it was present also on the lateral plasma membrane but was absent from the bile canalicular membrane. Within hepatocytes, the receptor was present in saccules of the Golgi complexes and occasionally in segments of the endoplasmic reticulum. Definite endocytic vesicles containing receptor were absent, and lysosomes were devoid of the receptor. These observations indicate that in the absence of exogenous asialoglycoprotein (a) the asialoglycoprotein receptor on the plasma membrane of hepatocytes is present only on the sinusoidal and lateral surfaces, (b) the receptor is being synthesized and assembled, (c) endocytic internalization of the receptor is minimal or absent, and (d) lysosomes are devoid of the receptor.

Animals↗
PubMed1995

Role of cytoskeleton and acidification of endocytic compartment in asialoglycoprotein metabolism in isolated rat hepatocyte couplets.

The process of receptor-mediated endocytosis is common to a variety of species and cell types. One of the best characterized receptor-ligand systems is the hepatocyte receptor for asialoglycoproteins. We investigated the morphological features of the uptake and intracellular transport of gold-conjugated asialofetuin in isolated rat hepatocyte couplets. We assessed the effects of colchicine, lumicolchicine, cytochalasin B, and chloroquine on the uptake and intracellular transport of asialoglycoproteins. Isolated rat hepatocyte couplets were incubated with gold-conjugated asialofetuin, and transmission electron micrographs of these cells were analyzed to determine the density and distribution of gold particles in the peripheral and pericanalicular areas. Results were analyzed morphometrically. Colchicine significantly inhibited the uptake and intracellular transport of asialoglycoproteins, but did not affect membrane fusion of endocytic compartments in the peripheral area. Lumicolchicine and cytochalasin B had minimal effects on these processes. Chloroquine inhibited the uptake of asialoglycoproteins, but did not affect the intracellular transport of asialoglycoproteins. Results suggest that the microtubule is essential for intracellular movement of endocytosed asialoglycoproteins and receptor recycling, and that endocytic structures in the peripheral regions can fuse in the absence of intact microtubules. We also found that uptake and intracellular transport of asialoglycoproteins were independent of the microfilaments, and the pH gradient in endocytic compartments was important in receptor-mediated endocytosis of asialoglycoproteins.

Acids↗
PubMed1990

The human hepatic asialoglycoprotein receptor is a target antigen for liver-infiltrating T cells in autoimmune chronic active hepatitis and primary biliary cirrhosis.

Autoantibodies to the human hepatic asialoglycoprotein receptor have been found in nearly 50% of the sera of patients with autoimmune chronic active hepatitis and in 15% of patients with primary biliary cirrhosis. In this study we demonstrate that the human hepatic asialoglycoprotein receptor is also a target antigen for T cell-mediated immune responses. Peripheral blood lymphocytes of 37% (7 of 19) of patients with autoimmune chronic active hepatitis and 33% (2 of 6) of patients with primary biliary cirrhosis showed a proliferative response to highly purified human hepatic asialoglycoprotein receptor, whereas no proliferation was found with peripheral blood lymphocytes of patients with chronic viral hepatitis (0 of 13) and healthy blood donors (0 of 4). Moreover, we isolated T-cell clones from liver biopsy samples of two patients with autoimmune chronic active hepatitis and two patients with peripheral blood lymphocytes. Between 2.8% and 14.3% of these clones showed a specific proliferative response to purified human hepatic asialoglycoprotein receptor. The response was restricted to autologous antigen-presenting cells and could be blocked by monoclonal antibodies against human leukocyte antigen-DR molecules. The response of T cells to the human hepatic asialoglycoprotein receptor did not require the lectinlike activity of the asialoglycoprotein receptor. Thus the human hepatic asialoglycoprotein receptor could be identified as a major target antigen of humoral and cellular immune reactions in autoimmune-mediated liver diseases.

Adult↗
PubMed1985

Characterization of the in vitro interaction of PNAhi lymphocytes with the bone marrow and hepatic asialoglycoprotein receptors.

We have previously identified an in vivo interaction between circulating PNAhi lymphoid cells and the hepatic asialoglycoprotein receptor, which results in a protracted liver sequestration of these cells. An in vitro frozen section binding assay was developed to study the interaction of PNAhi cells with the receptor in more detail. This assay confirmed that the sequestration of PNAhi lymphoid cells by the liver was mediated by the asialoglycoprotein receptor, as binding was inhibitable by coincubation with galactose, asialoglycoproteins, chelation of divalent cations, or a specific anti-asialoglycoprotein receptor antiserum. This frozen section binding assay was utilized to demonstrate the existence of a bone marrow asialoglycoprotein receptor which was found to be capable of binding to PNAhi lymphocytes or asialoglycoproteins bound to synthetic substrates. We further established that the bone marrow receptor differed both functionally and antigenically from its hepatic analogue.

Animals↗
PubMed1990

Antibodies against the hepatic asialoglycoprotein receptor perfused in situ preferentially attach to periportal liver cells in the rat.

Autoantibodies reacting with the galactose-specific hepatic asialoglycoprotein receptor--a liver-specific component expressed on the surfaces of hepatocytes--are often found in patients with chronic active hepatitis of presumed autoimmune origin. As part of an investigation into whether these anti-asialoglycoprotein receptor antibodies might be involved in the development of periportal liver damage in chronic active hepatitis, livers of ether-anesthetized rats were perfused in situ with polyclonal guinea pig anti-rabbit asialoglycoprotein receptor or murine monoclonal anti-human galactose-specific hepatic asialoglycoprotein receptor antibodies in excess at less than 8 degrees C or, as a control, with guinea pig anti-human plasma protein antibodies or normal guinea pig serum. Rapid (1 min) antegrade (by way of portal vein) or retrograde (through hepatic veins by way of vena cava) perfusions were performed in a nonrecirculating (once-through) mode in Ca+(+)-free medium. Blocks of liver tissue were immediately snap-frozen and the distribution of the antibody examined in cryostat sections by using an avidin-biotin immunohistochemical technique. In all of the perfusions with anti-asialoglycoprotein receptor (six antegrade, seven retrograde), the antibodies were found to be prominently and almost exclusively deposited on liver cells in the periportal areas. No deposition of immunoglobulins was detected in livers perfused with the control guinea pig sera. The findings suggest that the asialoglycoprotein receptor is expressed at high density mainly on cells in zone 1 of the hepatic lobule, and this may have implications for the development of periportal liver damage in chronic active hepatitis.

Animals↗
PubMed1980

Rat hepatocytes bind to synthetic galactoside surfaces via a patch of asialoglycoprotein receptors.

The binding of rat hepatocytes to flat polyacrylamide surfaces containing galactose is sugar-specific, requires Ca+2, and occurs only above a critical concentration of sugar in the substratum [Weigel et al., 1979, J. Biol. Chem., 254, 10,830). Binding is completely inhibited by asialo-orosomucoid but not by orosomucoid or asialo-agalacto-orosomucoid, suggesting that cell binding is mediated by asialoglycoprotein receptors. Asialo-orosomucoid was labeled with fluorescein isothiocyanate and used as a direct fluorescent probe to monitor the distribution of cell surface asialoglycoprotein receptors before and after hepatocyte binding to galactoside or control substrata. Cells bound at 37 degrees C were de-adhered at 4 degrees C using the Ca+2 chelator EGTA. The released cells were then stained with fluorescein-asialo-orosomucoid, fixed, washed, and examined by fluorescence microscopy. On freshly isolated cells before binding, the distribution of asialoglycoprotein receptors appears diffuse and nonclustered. However, more than half of the cells released intact from a galactoside surface had a single large (4 micrometer2) fluorescent patch. The receptor patch cannot be detected on cells while they are bound to a galactoside surface but rather only on released cells, indicating that the cell-substratum junction is the site of the receptor patch. No asialoglycoprotein receptor patches (less than or equal to 1%) were observed on cells that were incubated on, but did not bind to, an underivatized polyacrylamide surface or to a surface with a galactose concentration below the critical concentration for binding. Furthermore, no receptor patches were present on cells that had bound to and were subsequently released from substrata that did not contain galactose, including glass, tissue culture plastic, nontissue culture plastic, and collagen. The distribution of asialoglycoprotein receptors is preserved at 4 degrees C because at 37 degrees C the patches disappear with a half-life of approximately 2.6 min. The results directly demonstrate that a large cluster of asialoglycoprotein receptors mediates the binding of rat hepatocytes to a galactoside surface.

Animals↗
PubMed1992

Abnormal surface distribution of the human asialoglycoprotein receptor in cirrhosis.

Serum concentrations of asialoglycoproteins are increased in cirrhosis. We hypothesized that this increase results from abnormalities in the asialoglycoprotein receptor, which is located on the sinusoidal and lateral membrane of hepatocytes. Therefore we searched for morphological alterations in the distribution of the asialoglycoprotein receptor in human liver, using a light microscopic immunoperoxidase method in autopsy livers. In 24 of 25 (96%) of patients without liver disease, the asialoglycoprotein receptor was located on the sinusoidal and, less prominently, the lateral surface of hepatocytes but not the canalicular surface. In contrast, in 12 of 18 (67%) patients with cirrhosis of various causes, the receptor also was localized strikingly along the canalicular surface, with a corresponding decrease on the sinusoidal and lateral surfaces. We conclude that an abnormal cell-surface distribution of the asialoglycoprotein receptor commonly occurs in cirrhosis. This abnormality might result in impaired clearance of desialylated glycoproteins from plasma.

Asialoglycoprotein Receptor↗
PubMed1997

Lack of modulation of the galectin-3 and asialoglycoprotein receptor transcription in hepatocarcinoma of transgenic mice.

Galectin-3 and asialoglycoprotein receptor are lectins belonging to the classes of soluble lectins and of membrane C type lectins respectively. Conflicting results have been reported concerning their transcription level in the time course development of tumours. In the present study we investigated the abnormalities and the transcription levels of galectin-3 and asialoglycoprotein receptor genes in liver-targeted SV40 large T transgenic mice related to normal mice. In the strain expressing the highest level of large T, 100% of the male mice reproducibly developed an hepatocarcinoma. We provide evidence that the galectin-3 and asialoglycoprotein receptor genes are stable in such mice. The galectin-3 gene is weakly transcribed and its level is identical and constant in normal and transgenic mice, suggesting a lack of involvement in the development of large T-induced hepatocarcinoma. The asialoglycoprotein receptor gene is actively transcribed and its level remains high all along the development of the tumour; therefore, in such an hepatocarcinoma the asialoglycoprotein receptor could be used to take up drugs, genes or oligonucleotides associated with glycosylated carriers bearing galactose residues in a terminal non-reducing position.

Animals↗
PubMed1995

Synthesis of cluster galactosides with high affinity for the hepatic asialoglycoprotein receptor.

High-affinity ligands for the asialoglycoprotein receptor, which is uniquely localized on the parenchymal liver cell and recognizes oligoantennary galactosides, might be utilized as homing device to specifically target drugs or genes to parenchymal liver cells. In the present study, the synthesis of galactose-terminated triantennary glycosides, provided with various spacers between the beta-galactopyranosyl moieties and the branching point of the dendrite, is described. N-[Tris[[(methylthio)methoxy]methyl]methyl]-N alpha-[1-(6- methyladipy)]glycinamide (3b) was glycosylated with monogalactosyl derivatives, containing propanediol or ethylene glycol units as hydrophilic spacer moieties, to yield the corresponding cluster galactosides. To determine the affinity of the cluster galactosides for the asialoglycoprotein receptor, we have performed competition studies of [125I]ASOR binding, a specific ligand for the asialoglycoprotein receptor, to isolated parenchymal cells. The affinity for the asialoglycoprotein receptor significantly increased with increasing spacer length. N-[[[Tris-O-(beta-D-galactopyranosyl)-3,6,9-trioxaunde- canoxy]methoxy]methyl]-N-alpha-[1-(6-methyladipyl)]glycinami de (4e), a cluster galactoside provided with a 20 A spacer, possessed an at least 2000-fold higher affinity for the receptor than N-[[tris-O-(beta-D-galactopyranosyl)methyl]methyl]-N alpha-[1-(6- methyladipyl)]glycinamide (4a), a cluster galactoside lacking the spacer. It is concluded that vicinal galactosyl moieties within a cluster galactoside are more optimal recognized by the galactose binding sites of the asialoglycoprotein receptor upon proper spacing. The most potent galactoside, TG(20A), may constitute an attractive targeting device for the specific delivery of drugs and/or genes to the parenchymal liver cell.

Animals↗