scholarly journals Cyanidin 3-glucoside Is a Selective Inhibitor of Hepatic Bilirubin Uptake

2021 ◽  
Author(s):  
Paola Pelizzo ◽  
Marco Stebel ◽  
Nevenka Medic ◽  
Paola Sist ◽  
Andreja Vanzo ◽  
...  
Keyword(s):  
Membrane Transport ◽  
Protein Gene ◽  
Wistar Rat ◽  
Hepatic Uptake ◽  
Membrane Transporters ◽  
Basic Knowledge ◽  
Transport Pathways ◽  
Organ Specific ◽  
Rat Livers ◽  
Distinct Membrane

Abstract Background & Aims: One of the organ-specific functions of the liver is the excretion of bilirubin into the bile. Membrane transport of bilirubin from the blood to the liver is not only an orphan function, as there is no link to the protein/gene entities that carry it out, but also a poorly characterised function. The aim of this study was to investigate the pharmacology of bilirubin uptake in the liver of the female Wistar rat to improve basic knowledge in this neglected area of liver physiology.Methods: We treated isolated, perfused rat livers with repeated single-pass, albumin-free bilirubin boli. We monitored both bilirubin and bilirubin glucuronide in perfusion effluent with a biofluorometric assay. We tested the ability of nine molecules known to be substrates or inhibitors of sinusoidal membrane transporters to inhibit the hepatic uptake of bilirubin.Results: We found that cyanidin 3-glucoside and malvidin 3-glucoside are the only molecules that inhibit bilirubin uptake. These dietary anthocyanins resemble bromosulfophthalein (BSP), a substrate of several sinusoidal membrane transporters. The SLCO-specific substrates estradiol-17 beta-glucuronide, pravastatin, and taurocholate inhibited only bilirubin glucuronide uptake. Cyanidin 3-glucoside and taurocholate acted at physiological concentrations. The SLC22-specific substrates indomethacin and ketoprofen were inactive. We demonstrated the existence of a bilirubin glucuronide transporter that is inhibited by bilirubin, a fact reported only once in the literature.Conclusions: Data indicate that bilirubin and bilirubin glucuronide are transported into the liver via pharmacologically distinct membrane transport pathways. Some dietary anthocyanins may physiologically modulate the uptake of bilirubin into the liver.

Hepatic uptake of intact glutathione S-conjugate, inhibition by organic anions, and sinusoidal catabolism

1993 ◽  
Vol 265 (3) ◽  
pp. G547-G554
Author(s):  
C. A. Hinchman ◽  
A. T. Truong ◽  
N. Ballatori
Keyword(s):  
Guinea Pig ◽  
Rat Liver ◽  
Marked Decrease ◽  
Hepatic Uptake ◽  
Half Time ◽  
High Concentrations ◽  
Rat Livers ◽  
Dose Dependent ◽  
Uptake And Metabolism ◽  
Guinea Pig Liver

To identify potential mechanisms for hepatic removal of circulating glutathione (GSH) conjugates, uptake and metabolism of S-2,4-dinitrophenylglutathione (DNP-SG) were examined in isolated perfused livers from rat and guinea pig. Guinea pig livers perfused with 5 mumol of DNP-SG in a recirculating system (50 microM initial concn) rapidly cleared the conjugate from the perfusate (half time 3.7 min), whereas clearance was considerably slower in rat liver (half time 35 min). Disappearance of DNP-SG from the perfusate was accompanied by a simultaneous appearance of DNP-SG and its metabolites in bile. Addition of acivicin, an inhibitor of gamma-glutamyltransferase (gamma-GT), to the perfusate resulted in a marked decrease in DNP-SG clearance by guinea pig liver but had no effect in rat liver, suggesting that in the guinea pig this process is largely dependent on sinusoidal gamma-GT activity. However, even in the presence of acivicin, rat and guinea pig livers removed nearly one-half of the administered DNP-SG from the recirculating perfusate over 30 min. High concentrations of DNP-SG were found in bile (up to 3.7 mM), indicating that the liver is capable of transporting the intact conjugate from the circulation. When rat livers were perfused with higher concentrations of DNP-SG (100 and 250 microM), biliary excretion of DNP-SG increased dose dependently, with concentrations in bile reaching 10 mM at the higher dose. This was accompanied by a dose-dependent choleresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Propranolol metabolism by isolated hepatocytes from normal and cirrhotic rat livers: the effect of albumin

1990 ◽  
Vol 68 (6) ◽  
pp. 657-662 ◽  
Author(s):  
Louise Gariepy ◽  
Daphna Fenyves ◽  
Jean-Luc Petit ◽  
Ginette Raymond ◽  
Jean-Pierre Villeneuve
Keyword(s):  
Free Fraction ◽  
Rat Hepatocytes ◽  
Isolated Hepatocytes ◽  
Hepatic Uptake ◽  
Albumin Concentration ◽  
Isolated Rat Hepatocytes ◽  
Subsequent Elimination ◽  
Rat Livers ◽  
Mediated Catalysis ◽  
Isolated Rat

Several recent reports have shown that the hepatic uptake and subsequent elimination of some substrates is faster in the presence of albumin than in its absence, as if some of the substrate bound to albumin was also available for uptake. In the present study, we examined the effect of albumin on the clearance of propranolol by isolated rat hepatocyte suspensions. The clearance of total drug decreased progressively as albumin concentration increased. There was also a progressive decrease in the free fraction of propranolol and the net result was an increase in the clearance of unbound drug (+50% at 40 g/L albumin). This increase was not due to an oncotic pressure effect of albumin, nor to the presence of fatty acids bound to albumin. The clearance of propranolol by isolated hepatocytes from cirrhotic rats was decreased compared with controls (−50%), and albumin also increased propranolol free clearance, albeit to a lesser extent than in control animals. Our results indicate that albumin facilitates the elimination of propranolol by hepatocytes, possibly because of surface-mediated catalysis of the albumin–propranolol complexes.Key words: propranolol clearance, albumin, isolated rat hepatocytes, cirrhosis.

Specificity of Classical and Putative Cl- Transport Inhibitors on Membrane Transport Pathways in Human Erythrocytes

2003 ◽  
Vol 13 (4) ◽  
pp. 181-188 ◽  
Author(s):  
Steven Culliford ◽  
Clive Ellory ◽  
Hans-Jochen Lang ◽  
Heinrich Englert ◽  
Hery Staines ◽  
...  
Keyword(s):  
Membrane Transport ◽  
Human Erythrocytes ◽  
Transport Pathways ◽  
Transport Inhibitors

scholarly journals Steatosis Alters the Activity of Hepatocyte Membrane Transporters in Obese Rats

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2733
Author(s):  
Catherine M Pastor ◽  
Valérie Vilgrain
Keyword(s):  
Contrast Agent ◽  
Experimental Model ◽  
Liver Diseases ◽  
Gadobenate Dimeglumine ◽  
Membrane Transporters ◽  
Liver Imaging ◽  
Fat Accumulation ◽  
Obese Rats ◽  
Rat Livers ◽  
Gamma Counter

Fat accumulation (steatosis) in ballooned hepatocytes alters the expression of membrane transporters in Zucker fatty (fa/fa) rats. The aim of the study was to quantify the functions of these transporters and their impact on hepatocyte concentrations using a clinical hepatobiliary contrast agent (Gadobenate dimeglumine, BOPTA) for liver imaging. In isolated and perfused rat livers, we quantified BOPTA accumulation and decay profiles in fa/+ (normal) and fa/fa hepatocytes by placing a gamma counter over livers. Profiles of BOPTA accumulation and decay in hepatocytes were analysed with nonlinear regressions to characterise BOPTA influx and efflux across hepatocyte transporters. At the end of the accumulation period, BOPTA hepatocyte concentrations and influx clearances were not significantly different in fa/+ and fa/fa livers. In contrast, bile clearance was significantly lower in fatty hepatocytes while efflux clearance back to sinusoids compensated the low efflux into canaliculi. The time when BOPTA cellular efflux impacts the accumulation profile of hepatocyte concentrations was slightly delayed (2 min) by steatosis, anticipating a delayed emptying of hepatocytes. The experimental model is useful for quantifying the functions of hepatocyte transporters in liver diseases.

scholarly journals Function Analysis of Choline Binding Domains of LytA, LytC and CbpD in The Biofilm Formation Process of Streptococcus Pneumoniae

2021 ◽  
Author(s):  
Hongsheng Ji ◽  
Yingshun Zhou ◽  
Luhua Zhang ◽  
Ying Wang ◽  
Feiyang Zhang ◽  
...  
Keyword(s):  
Membrane Transport ◽  
Biofilm Formation ◽  
Function Analysis ◽  
Amino Sugar ◽  
Extracellular Dna ◽  
Transport Pathways ◽  
Binding Domains ◽  
Phenotype Analysis ◽  
High Concentrations

Abstract Background: Choline binding proteins (CBPs) are a family of proteins that can interact with pneumococcal cell wall by choline binding domains (CBDs). In this study, we found a modified choline binding repeat (ChBp-I) with a pI of 7.66 can promote the development of biofilm in vitro. Thus, we aim to characterize the function of CBDs of LytA, LytC and CbpD in biofilm formation.Results: By transcriptome analysis, 81 genes were identified as down regulated and 138 genes were up regulated (|log2 fold change|≥1.5) under ChBp-I of 50mg/L. The up regulated genes are well clustered in membrane transport (carbohydrate, lipid, protein, cation and phosphate) and carbohydrate metabolism (fructose, mannose, galactose, starch, sucrose, amino sugar and nucleotide) related pathways. The up-regulated genes are mostly regulated the same under CBD-A, CBD-C and CBD-D. Phenotype analysis reveal high concentrations of CBD-C and CBD-D (>100μg/mL) but not CBD-A (negative charged) can promote the biofilm formation. Meanwhile, the existence of CBD-C and CBD-D promote the growth rate and both CBDs inhibit the autolysis of pneumococcal cell. By component analysis, these three CBDs were proved involved in the regulation of extracellular DNA, protein, cation and phosphate, and promote the forming of insoluble precipitates.Conclusions: The binding of CBPs can influence the membrane transport pathways and react with extracellular DNA and protein to promote biofilm formation in S. pneumoniae.

Proliferating cell nuclear antigen expression in Wistar rat livers

1994 ◽  
Vol 46 (2) ◽  
pp. 105-110 ◽  
Author(s):  
Elias Perentes ◽  
Jacqueline Arnold ◽  
Gabriele Meier ◽  
Robert A. Ettlin ◽  
Eva Karamitopoulou ◽  
...  
Keyword(s):  
Proliferating Cell Nuclear Antigen ◽  
Antigen Expression ◽  
Wistar Rat ◽  
Nuclear Antigen ◽  
Proliferating Cell ◽  
Rat Livers

Role of bicarbonate in biliary excretion of diisothiocyanostilbene disulfonate

1988 ◽  
Vol 255 (6) ◽  
pp. G713-G722
Author(s):  
M. S. Anwer ◽  
K. Nolan ◽  
W. G. Hardison
Keyword(s):  
Biliary Excretion ◽  
Rat Hepatocytes ◽  
Hepatic Uptake ◽  
Disulfonic Acid ◽  
Base Line ◽  
Hepatic Transport ◽  
Isolated Rat Hepatocytes ◽  
Canalicular Membrane ◽  
Major Mechanism ◽  
Rat Livers

Hepatic transport of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) was studied in isolated perfused rat livers and in isolated rat hepatocytes to determine if DIDS-induced decrease in biliary HCO3- excretion is due to a DIDS-HCO3- exchange and/or due to inhibition of Cl(-)-HCO3- exchange. In isolated perfused rat livers, DIDS reversibly decreased biliary HCO3- concentration and excretion. The changes in biliary HCO3- concentration were inversely related to biliary DIDS concentration. DIDS was concentrated in bile, indicating active hepatic transport. Replacement of perfusate HCO3- with equimolar dimethyloxazolidinedione (DMO) or tricine decreased biliary excretion, but not hepatic uptake, of DIDS. Biliary excretion of DIDS was also associated with a decrease in bile pH, and this decrease in pH was greater in the presence of HCO3-. HCO3-, but not DMO or tricine, stimulated DIDS efflux from preloaded hepatocytes. DIDS efflux was also temperature dependent and increased with increasing extracellular pH. Collectively, these results are consistent with the presence of a DIDS-HCO3- (OH-) exchange mechanism at the canalicular membrane. HCO3(-)-dependent Cl- uptake in hepatocytes was competitively inhibited by DIDS (Ki = 0.24 mM), confirming the presence of DIDS-inhibitable Cl(-)-HCO3- exchange. However, the ability of DIDS to decrease biliary HCO3- excretion persisted when perfusate Cl- was replaced by isethionate. Moreover, biliary HCO3- concentration returned to base line despite the presence of 2-6 mM DIDS in bile. Thus it seems unlikely that the inhibition of Cl(-)-HCO3- exchange by DIDS is a major mechanism of inhibition of HCO3- excretion. We, therefore, conclude that a DIDS-HCO3- (OH-) exchange at the canalicular membrane is the most likely explanation for the observed decrease in biliary HCO3- excretion.

scholarly journals The role of conjugation reactions in enhancing biliary secretion of bile acids

1983 ◽  
Vol 214 (3) ◽  
pp. 923-927 ◽  
Author(s):  
D A Vessey ◽  
J Whitney ◽  
J L Gollan
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Hepatic Uptake ◽  
Biliary Secretion ◽  
Side Chain ◽  
Isolated Perfused Rat Liver ◽  
Rat Livers ◽  
Kinetics Of ◽  
Methylene Group

Shortening the five-carbon carboxylic acid side chain of cholic acid by one methylene group gave rise to a bile acid (norcholate) that was not a substrate for the bile acid-conjugating enzymes. The metabolism and biliary secretion of norcholate in intact liver was examined in the isolated perfused rat liver system. When rat livers were perfused with 14-20 microM solutions of norcholate for 10 min, norcholate was found in the unconjugated form in liver, venous effluent and bile. Neither tauronorcholate nor glyconorcholate was detectable by high-pressure liquid chromatography or fast-atom-bombardment mass spectrometry. The kinetics of hepatic uptake and biliary secretion of norcholate was compared with that for cholate, taurocholate and chemically synthesized tauronorcholate. The latter three bile acids were completely cleared from the perfusate and efficiently secreted into the bile. However, norcholate was incompletely extracted from the perfusate, and this was shown to be at least partially due to its relatively lower rate of hepatic uptake. Furthermore, the rate of norcholate secretion into bile was greatly reduced relative to the secretion of cholate or chemically synthesized tauronorcholate, even though the concentration of norcholate in the liver was comparatively high. These data demonstrate that the conjugation of bile acids greatly facilitates their secretion into bile.

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