Regulation of rat hepatocyte organic anion transport activity by bile acids

Hepatology ◽  
1993 ◽  
Vol 18 (4) ◽  
pp. A138
Author(s):  
K ISHII
Keyword(s):  
Bile Acids ◽  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Transport Activity ◽  
Rat Hepatocyte ◽  
Anion Transport Activity

scholarly journals A recurrent ABCC2 p.G693R mutation resulting in loss of function of MRP2 and hyperbilirubinemia in Dubin-Johnson syndrome in China

2020 ◽  
Author(s):  
Lina Wu ◽  
Yanmeng Li ◽  
Yi Song ◽  
Donghu Zhou ◽  
Siyu Jia ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Organic Anion ◽  
Autosomal Recessive Disorder ◽  
Anion Transport ◽  
Causative Mutation ◽  
Loss Of Function ◽  
Organic Anion Transport ◽  
Transport Activity ◽  
Johnson Syndrome ◽  
Anion Transport Activity

Abstract Background: Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by predominantly conjugated hyperbilirubinemia that is caused by pathogenic mutations in the adenosine triphosphate-binding cassette subfamily C member 2 ( ABCC2 ) gene, which encodes multidrug resistance-associated protein 2 (MRP2). However, little is known about the causative mutation of DJS in China. Recently, we have reported ABCC2 p.G693R mutation in two unrelated cases. In the present study, we investigated the pathogenicity of the ABCC2 p.G693R mutation in DJS in China. Methods: Clinical and genetic analysis was conducted for the two patients with the ABCC2 p.G693R mutation. Whole exome sequencing for mutations in other known hyperbilirubinemia-related genes was conducted for the cases with ABCC2 p.G693R. Expression and cellular localization of the mutant MRP2 p.G693R were analyzed by Western blotting and immunofluorescence assay, respectively. Organic anion transport activity was evaluated by the analysis of glutathione-conjugated-monochlorobimane. Results: The two DJS patients with ABCC2 p.G693R mutation, which was conserved among different species, showed typical hyperbilirubinemia phenotype. No pathogenic mutation was identified in the other known hyperbilirubinemia related genes. Functional studies in three cell lines showed that the expression, localization and the organic anion transport activity were significantly compromised by MRP2 p.G693R mutation compared with wild-type MRP2. Conclusions: The recurrent ABCC2 p.G693R mutation is associated with loss of function of the MRP2 protein and may result in hyperbilirubinemia in DJS in China.

Redistribution of canalicular organic anion transport activity in isolated and cultured rat hepatocytes

Hepatology ◽  
1995 ◽  
Vol 21 (6) ◽  
pp. 1649-1657 ◽  
Author(s):  
Han Roelofsen ◽  
Conny T. M. Bakker ◽  
Berry Schoemaker ◽  
Marc Heijn ◽  
Peter L. M. Jansen ◽  
...  
Keyword(s):  
Organic Anion ◽  
Rat Hepatocytes ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Transport Activity ◽  
Cultured Rat Hepatocytes ◽  
Anion Transport Activity

scholarly journals A novel ABCC2 p.G693R mutation resulting in loss of function of MRP2: a recurrent cause of hyperbilirubinemia in Dubin-Johnson syndrome in China

2019 ◽  
Author(s):  
Lina Wu ◽  
Yanmeng Li ◽  
Yi Song ◽  
Donghu Zhou ◽  
Siyu Jia ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Organic Anion ◽  
Autosomal Recessive Disorder ◽  
Anion Transport ◽  
Causative Mutation ◽  
Loss Of Function ◽  
Organic Anion Transport ◽  
Transport Activity ◽  
Johnson Syndrome ◽  
Anion Transport Activity

Abstract Background Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by predominantly conjugated hyperbilirubinemia that is caused by pathogenic mutations in the adenosine triphosphate-binding cassette subfamily C member 2 ( ABCC2 ) gene, which encodes multidrug resistance-associated protein 2 (MRP2). However, little is known about the causative mutation of DJS in China. Recently, we have reported a novel ABCC2 p.G693R mutation in two unrelated cases. In the present study, we investigated the pathogenicity of the ABCC2 p.G693R mutation in DJS in China.Methods Clinical and genetic analysis was conducted for the two patients with the ABCC2 p.G693R mutation. Whole exome sequencing for mutations in other known hyperbilirubinemia-related genes was conducted for the cases with ABCC2 p.G693R. Expression and cellular localization of the mutant MRP2 p.G693R were analyzed by Western blotting and immunofluorescence assay, respectively. Organic anion transport activity was evaluated by the analysis of glutathione-conjugated-monochlorobimane.Results The two DJS patients with ABCC2 p.G693R mutation, which was conserved among different species, showed typical hyperbilirubinemia phenotype. No pathogenic mutation was identified in the other known hyperbilirubinemia related genes. Functional studies in three cell lines showed that the expression, localization and the organic anion transport activity were significantly compromised by MRP2 p.G693R mutation compared with wild-type MRP2.Conclusions The ABCC2 p.G693R mutation is associated with loss of function of the MRP2 protein, which may represent one of the major etiological factors of hyperbilirubinemia in DJS in China.

Mechanism of bile acid facilitation of biliary protoporphyrin excretion in rat liver

1995 ◽  
Vol 268 (5) ◽  
pp. G754-G763 ◽  
Author(s):  
M. M. Berenson ◽  
M. Y. el-Mir ◽  
L. K. Zhang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Intracellular Transport ◽  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Canalicular Membrane ◽  
Rat Livers ◽  
Eisai Hyperbilirubinemic Rat

The mechanism(s) by which bile acids increase biliary protoporphyrin excretion was characterized using perfused rat livers. We determined 1) relationships between biliary bile acids, phospholipid, and protoporphyrin, using rapid kinetic analyses; 2) protoporphyrin excretion in livers with defective canalicular multispecific organic anion transport; 3) effects of intracellular vesicular transport inhibition with colchicine and monensin; and 4) the role of luminal bile acids, using retrograde intrabiliary taurocholate injections. Biliary protoporphyrin excretion peaked with phospholipid excretion 14-18 min after loading. Protoporphyrin excretion induced by taurocholate was not related to effects on intracellular transport, including colchicine- and monensin-inhibitable vesicular systems. Eisai hyperbilirubinemic rat livers excreted protoporphyrin similarly to controls. Retrograde intrabiliary taurocholate injections increased protoporphyrin output. Collectively, these data suggest that 1) intracellular protoporphyrin transport is mediated by nonvesicular carriers targeted to the canalicular membrane, and 2) bile acid facilitates protoporphyrin translocation into bile in the same manner it effects phospholipid excretion.

Impaired hepatocanalicular organic anion transport in endotoxemic rats

1995 ◽  
Vol 269 (3) ◽  
pp. G427-G434 ◽  
Author(s):  
H. Roelofsen ◽  
B. Schoemaker ◽  
C. Bakker ◽  
R. Ottenhoff ◽  
P. L. Jansen ◽  
...  
Keyword(s):  
Organic Anion ◽  
Liver Perfusion ◽  
Isolated Hepatocytes ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Transport Activity ◽  
Efflux Rate ◽  
And Control ◽  
Dose Dependent ◽  
Isolated Liver

To investigate the mechanism of sepsis-associated hyperbilirubinemia we have studied hepatocanalicular transport of organic anions in a rat model of endotoxemia. Rats were injected intravenously with lipopolysaccharides (LPS), and at different times after injection, canalicular transport of 2,4-dinitrophenyl-S-glutathione (GS-DNP), as a model organic anion, was measured in perfused livers and isolated hepatocytes. In isolated liver perfusion experiments the initial biliary GS-DNP secretion rate was found to be significantly decreased 18 h after injection with 2 mg/kg LPS. In isolated hepatocytes from these rats, GS-DNP efflux rate was also significantly decreased (193.0 +/- 67 and 448.3 +/- 53 nmol.min-1.g dry wt-1 in endotoxemic and normal hepatocytes, respectively). Inhibition of GS-DNP effluxin isolated endotoxemic hepatocytes was dose dependent and reached a maximum with 0.25 mg/kg LPS. Inhibition was maximal at 12 h after LPS injection. Transport activity gradually returned to normal in 4-5 days after endotoxemia was induced. Dexamethasone pretreatment partially reversed the inhibition of GS-DNP transport in isolated endotoxemic hepatocytes. The phorbol ester phorbol 12-myristate 13-acetate increased GS-DNP efflux by 73 +/- 16 and 24 +/- 8% in endotoxemic and control hepatocytes, respectively, but could not restore the transport activity of endotoxemic hepatocytes to control levels. These results show that canalicular organic anion transport is decreased in the endotoxemic liver; this may play a role in the frequently observed hyperbilirubinemia during sepsis.

ATP-dependent multispecific organic anion transport system in rat erythrocyte membrane vesicles

1992 ◽  
Vol 262 (1) ◽  
pp. C104-C110 ◽  
Author(s):  
M. Heijn ◽  
R. P. Oude Elferink ◽  
P. L. Jansen
Keyword(s):  
Bile Acids ◽  
Transport System ◽  
Organic Anion ◽  
Membrane Vesicles ◽  
Organic Anions ◽  
Anion Transport ◽  
Maximal Velocity ◽  
Organic Anion Transport ◽  
Anion Transporter ◽  
Anion Transport System

The uptake of oxidized glutathione (GSSG) into inside-out membrane vesicles of Wistar rat erythrocytes was studied. Uptake was ATP dependent, into an osmotically active space, and saturable. Analysis of saturable ATP-dependent GSSG uptake showed two affinities for GSSG [concentration for half-maximal velocity (K1/2 1), 26 microM; K 1/2 2, 4 mM; maximum transport rate (Vmax 1), 100 pmol.mg-1.min-1; Vmax 2, 360 pmol.mg-1.min-1]. Interactions of the high-affinity system with different organic compounds were studied. Leukotriene C4, bromosulfophthalein-S-glutathione, and 2,4-dinitrophenyl-S-glutathione were effective inhibitors. In addition, anionic nonglutathione conjugates, like indocyanine green, rose bengal, dibromosulfophthalein, and sulfated or glucuronidated (divalent) bile acids inhibited GSSG transport. Monovalent bile acids had no influence on GSSG transport. Inhibition by 2,4-dinitrophenyl-S-glutathione [inhibition constant (Ki) = 2.6 microM] and sulfated glycolithocholic acid (Ki = 2.9 microM) was purely competitive. The use of adenosinetriphosphatase (ATPase) inhibitors suggested a resemblance with E1E2-type ATPase. Vesicles of erythrocytes isolated from the TR- rat, a mutant rat strain with a defective biliary secretion of organic anions, have an impaired uptake of GSSG (Vmax was decreased 2-fold). In conclusion, erythrocytes have an ATP-dependent organic anion transport system that can be inhibited by a broad range of organic anions. This system is very similar if not identical to the hepatocanalicular ATP-dependent organic anion transporter.

scholarly journals Characteristics of bile salt uptake into skate hepatocytes

1994 ◽  
Vol 299 (3) ◽  
pp. 665-670 ◽  
Author(s):  
G Fricker ◽  
V Dubost ◽  
K Finsterwald ◽  
J L Boyer
Keyword(s):  
Substrate Specificity ◽  
Bile Salt ◽  
Transport System ◽  
Bile Salts ◽  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Salt Uptake ◽  
Anion Transport System ◽  
Alpha 7

The substrate specificity for the transporter that mediates the hepatic uptake of organic anions in freshly isolated hepatocytes of the elasmobranch little skate (Raja erinacea) was determined for bile salts and bile alcohols. The Na(+)-independent transport system exhibits a substrate specificity, which is different from the specificity of Na(+)-dependent bile salt transport in mammals. Unconjugated and conjugated di- and tri-hydroxylated bile salts inhibit uptake of cholyltaurine and cholate competitively. Inhibition is significantly greater with unconjugated as opposed to glycine- or taurine-conjugated bile salts. However, the number of hydroxyl groups in the steroid moiety of the bile salts has only minor influences on the inhibition by the unconjugated bile salts. Since the transport system seems to represent an archaic organic-anion transport system, other anions, such as dicarboxylates, amino acids and sulphate, were also tested, but had no inhibitory effect on bile salt uptake. To clarify whether bile alcohols, the physiological solutes in skate bile, share this transport system, cholyltaurine transport was studied after addition of 5 beta-cholestane-3 beta,5 alpha,6 beta-triol, 5 alpha-cholestan-3 beta-ol and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol. These bile alcohols inhibit cholyltaurine uptake non-competitively. In contrast, uptake of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, which is Na(+)-independent, is not inhibited by cholyltaurine. The findings further characterize a Na(+)-independent organic-anion transport system in skate liver cells, which is not shared by bile alcohols and has preference for unconjugated lipophilic bile salts.

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