Heterogeneity of rat hepatocytes in transport and hepatic binding of asialo-alkaline phosphatase studied after induction of selective acinar damage by N-hydroxy-2-acetylaminofluorene and carbon tetrachloride

Groothuis, Geny M. M.; Weitering, J.G.; Hardonk, M. J.; Meijer, Dirk K. F.

doi:10.1016/0006-2952(83)90082-5

Cited by 9 publications

(7 citation statements)

References 20 publications

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“…Earlier studies by Evarts, Marsden and Thorgeirsson (32) (by indirect immunofluorescent staining of rat liver sections with anti-ASGP-R antibodies) and by Hardonk and colleagues in Gronigen (33, 34), who examined the distribution of canine intestinal alkaline phosphatase (a galactoseterminating glycoprotein) after either direct binding to rat liver sections or intravenous injection in the intact animal, suggested a predominantly centrilobular distribution of the ASGP-R. However, subsequent transport studies by the Gronigen group indicated a higher uptake of canine intestinal alkaline phosphatase by zone 1 hepatocytes (35). More recently, the latter group has investigated the uptake of another ligand, asialoorosomucoid (ASOR), during ex uiuo recirculating perfusion of livers of Iarge rats (320 to 360 gm body weight) (36).…”

Section: Fig 4 High-power Views Of Rat Liver After Immunohistochemimentioning

confidence: 99%

Antibodies Against the Hepatic Asialoglycoprotein Receptor Perfused In Situ Preferentially Attach to Periportal Liver Cells in the Rat

et al. 1990

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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.

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Section: Fig 4 High-power Views Of Rat Liver After Immunohistochemimentioning

confidence: 99%

Antibodies Against the Hepatic Asialoglycoprotein Receptor Perfused In Situ Preferentially Attach to Periportal Liver Cells in the Rat

et al. 1990

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“…Since various cell types may 'compete' for the same substrate, dose dependency should be taken into account in measuring the relative clearance of macromolecules by the various cell types, as well as cell-specific drug targeting with glycoproteins [12, 97,118] , Acinar Heterogeneity in Protein Disposition The distribution of the above-mentioned receptor systems on the cell surfaces along the sinusoids is not well known. Some ear lier reports provided evidence for a hetero geneous acinar binding of asialo-alkaline phosphatase, preferentially in zone 3 [36,37], epidermal growth factor [35] and asialoorosomucoid (ASOR) in zone 1 [12] in rat liver, whereas insulin, IgA and apolipoprotein B are homogeneously distributed upon injection [116]. The finding of McFarlane et al [125] that antibodies against the ASGP receptor predominantly bind in zone 1 is in contradiction with the results of van der Sluijs et al who further investi gated the acinar distribution of the ASGPprocessing system using 125I-ASOR in antegradely and retrogradely perfused rat livers, by performing quantitative autoradiography [12], A gradient was observed descending from zone-1 to zone-3 cells upon perfusion in the normal direction.…”

Section: Endocytosis Of Proteinsmentioning

confidence: 99%

“…As most drugs and xenobiotics are more or less water-soluble com pounds, special precautions are necessary to Separation of Isolated Hépatocytes prevent diffusion of the compound during processing. For radioactive substrates a spe cial technique of freeze autoradiography can be successfully applied [22,25,33], For fluo rescent substrates the localization can be de tected on air-dried frozen sections using the fluorescence microscope [18,20,21,26,34], For the localization of transport of proteins, conventional autoradiography after fixation of the tissue can be applied for 125I-labelled proteins [12,35], Fluorescence microscopy for FITC-labelled proteins and (immuno)-histochemical techniques [36,37] can be ap plied. In some studies with bile acids, the bile acid was either derivatized with a tripep tide to be fixed [38,39] or with a fluorescent label to be detectable by fluorescent micros copy [40], but here it remains difficult to prove that the labelled substrates behave kinetically identically with the unlabelled sub strate.…”

Section: Localization Of Substrates In the Acinusmentioning

confidence: 99%

“…There fore it is critical to determine the selectivity and extent of the damage in each set of experiments with a given dose of toxin. In drug transport studies N-hydroxy-2-acetylaminofluorene [36,56,57] and allylalcohol [7] are used as zone-1 toxins, and carbon tetrachloride [7,36,56, 57] and bromobenzene [7,58] as zone-3 toxins. Some of these studies have yielded results that are compat ible with those obtained with other tech niques [7].…”

Section: Selective Zonal Toxicity Pharmacokinetic Modellingmentioning

confidence: 99%

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Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

Groothuis¹,

Meijer²

1992

Enzyme

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In the past two decades many studies have been devoted to the involvement of the periportal (zone-1) and perivenous (zone-3) hepatocytes in bile formation and hepatobiliary transport of endogenous and exogenous compounds. It became clear that such a heterogeneity in transport function can, in principle, be due to the different localization of the cells in the acinus with respect to the incoming blood, to intrinsic differences between the cells or to both. In this review we first discuss the techniques used to study hepatocyte heterogeneity in hepatobiliary transport function. Combinations of such techniques can be used to discriminate between cellular heterogeneity due to acinar localization as opposed to intrinsic differences. These techniques include: normal and retrograde perfusions of isolated perfused livers; autoradiographic, fluorimetrie and histochemical localization of injected substrates; separation of isolated hepatocytes into fractions enriched in periportal and perivenous cells; measurements of fluorescent surface signals with microlight guides; selective zonal toxicity, and pharmacokinetic modelling and analysis. Subsequently, for each of the rate-limiting steps in the hepatobiliary transport of organic compounds, the basic mechanisms are summarized and the available knowledge on the involvement of the cells from the various zones in these transport steps is discussed. The available literature data indicate that heterogeneity in transport function is often due to the localization of the cells in the acinus: the periportal cells are the first to come into contact with the portal blood and are thus exposed to the highest substrate concentration. Consequently they obtain the most prominent task in further disposition of the particular compound. It follows that the extent of involvement of the perivenous cells in drug disposition is implicitly determined by the activity of the periportal cells. Because of the potential saturation of elimination processes in the periportal cells, the involvement of perivenous cells may vary with the input concentration. In addition, real intrinsic differences have been established in the hepatobiliary transport of some substrates. These are probably based on differences in the cellular content of carrier- and receptor-binding and/or metabolizing proteins. In some cases these intrinsic differences may be secondary to existing sinusoidal gradients of endogenous compounds, such as O(2), amino acids, bile acids or monosaccharides. Yet, data on the heterogeneity of hepatocytes in the various transport steps are far from complete or are even totally lacking, especially for human liver. A multi-experimental approach and advanced technology will be needed in the future to gain more insight into the acinar organization of bile formation and hepatobiliary transport of drugs in the human.

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“…Transport experiments of Groothuis et al (20) suggested a higher uptake rate in zone 1 of the ASGP dog intestinal alkaline phosphatase (21). These and other authors (20)(21)(22), however, also showed preferential binding of this ASGP to zone 3 hepatocytes in enzyme histochemical studies. Binding to this hepatocyte subpopulation could be inhibited completely by pretreatment of the rats with the selective zone 3 toxin carbon tetrachloride (20), but hepatic uptake was not affected by this pretreatment.…”

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confidence: 82%

Heterogeneous acinar localization of the asialoglycoprotein internalization system in rat hepatocytes

et al. 1988

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Desialylated glycoprotein is rapidly cleared from plasma by a receptor-mediated endocytic mechanism located on hepatocytes. We studied the hepatic acinar distribution of this asialoglycoprotein transport system with the ligand 125I-asialoorosomucoid using rat liver perfused in either antegrade or retrograde direction in combination with quantitative light microscopic autoradiography. Grain distribution along the acinus appeared dependent on the perfusion direction. A rather shallow zone 1 to zone 3 gradient was observed if livers were perfused in the normal direction. However, a statistically significantly steeper zone 3 to zone 1 gradient was detected in retrograde perfusions. Kinetic analysis of perfusate clearance profiles yielded a hepatic clearance of 21.6 +/- 1.3 ml per min in antegradely perfused liver. Hepatic extraction was calculated to be 60.1 +/- 7.4%. Biliary secretion of radioactivity amounted to 1.89 +/- 0.18% of the dose within 1 hr after injection and consisted of intact material (1.39 +/- 0.25%) and radioactive low-molecular-weight degradation products (0.52 +/- 0.08%), of which more than 90% could be accounted for by 125I-. Apart from a minor difference regarding biliary secretion of an unidentified glycopeptide (less than 0.1% of the injected dose), transport data for the retrogradely perfused livers were identical to those obtained with livers perfused in antegrade direction, emphasizing the functional equivalence of both groups of livers. The autoradiographic data indicate that zone 3 hepatocytes take up 125I-asialoorosomucoid more avidly than zone 1 cells. The kinetic and biochemical data indicate that further processing in the hepatocytes is virtually similar in the two zones.(ABSTRACT TRUNCATED AT 250 WORDS)

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Heterogeneity of rat hepatocytes in transport and hepatic binding of asialo-alkaline phosphatase studied after induction of selective acinar damage by N-hydroxy-2-acetylaminofluorene and carbon tetrachloride

Cited by 9 publications

References 20 publications

Antibodies Against the Hepatic Asialoglycoprotein Receptor Perfused In Situ Preferentially Attach to Periportal Liver Cells in the Rat

Antibodies Against the Hepatic Asialoglycoprotein Receptor Perfused In Situ Preferentially Attach to Periportal Liver Cells in the Rat

Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

Heterogeneous acinar localization of the asialoglycoprotein internalization system in rat hepatocytes

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