Chronic Idiopathic Jaundice With Unidentified Pigment in Liver Cells

Dubin, I. N.; Johnson, Frank B.

doi:10.1097/00005792-195409000-00001

Cited by 410 publications

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“…Mrp2-deficient rats (TR Ϫ and EHBR) and their transport-competent counterparts serve as useful models to study the effects of Mrp2 on drug disposition, and provide a rodent model for human DubinJohnson syndrome (Dubin and Johnson, 1954;Jansen et al, 1985). However, several other important biochemical differences exist between the mutant and wild-type rats that must be considered, and the current study was designed to characterize the differences in protein expression of several key transport proteins and UGT1a in multiple tissues from Wistar transport-competent and Mrp2-deficent (TR Ϫ ) rats using semiquantitative Western blot analysis.…”

Section: Discussionmentioning

confidence: 99%

“…A similar mutation also exists in the Sprague-Dawley strain of rats, where the Mrp2-deficient mutant is referred to as Eisai hyperbilirubinemic rats, or EHBRs (Hirohashi et al, 1998). TR Ϫ and EHBR rats provide an animal model for human Mrp2 deficiency, Dubin-Johnson syndrome, a condition characterized by mild chronic conjugated hyperbilirubinemia (Dubin and Johnson, 1954;Kartenbeck et al, 1996). Mrp2-deficient rats also exhibit elevated serum bile acid concentrations, alterations in bile composition, and reduced bile flow (Jansen et al, 1985).…”

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confidence: 99%

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Characterization of Transport Protein Expression in Multidrug Resistance-Associated Protein (Mrp) 2-Deficient Rats

Johnson¹,

Zhang²,

Schuetz³

et al. 2006

Drug Metabolism and Disposition

106

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Characterization of Transport Protein Expression in Multidrug Resistance-Associated Protein (Mrp) 2-Deficient Rats

Johnson¹,

Zhang²,

Schuetz³

et al. 2006

Drug Metabolism and Disposition

106

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“…In TR − rats the cMoat gene was found to bear a single nucleotide deletion resulting in a stop codon and absence of the cMoat protein [4,6]. Humans who have an autosomal-recessive liver disorder characterized by chronic conjugated hyperbilirubinaemia and impaired hepatobiliary transport of non-bile-salt organic anions, called Dubin-Johnson syndrome, share a similar phenotype to the GY\TR − mutant rats [10,11]. Interestingly, the molecular mechanism of this rare, but benign, disease has been associated Abbreviations used : cMoat/cMOAT, mouse and human canalicular multispecific organic anion transporters, respectively ; GCS-HS, γ-glutamylcysteine synthetase heavy-subunit gene ; GY/TR − or TR − rat, Groningen yellow/transport-deficient rat ; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid ; DTNB, 5,5h-dithiobis-(2-nitrobenzoic acid) ; ACO, fatty acyl-CoA oxidase ; CAT, carnitine acetyl-CoA transferase ; GAPDH, glyceraldehyde-3-phosphate dehydrogenase ; LAP, leucine aminopeptidase.…”

Section: Introductionmentioning

confidence: 99%

Induction of the multispecific organic anion transporter (cMoat/mrp2) gene and biliary glutathione secretion by the herbicide 2,4,5-trichlorophenoxyacetic acid in the mouse liver

Wielandt

Vollrath

Manzano

et al. 1999

Biochemical Journal

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The canalicular multispecific organic anion transporter, cMoat, is an ATP-binding-cassette protein expressed in the canalicular domain of hepatocytes. In addition to the transport of endo- and xenobiotics, cMoat has also been proposed to transport GSH into bile, the major driving force of bile-acid-independent bile flow. We have shown previously that the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), a peroxisome-proliferator agent, significantly increases bile-acid-independent bile flow in mice. On this basis, the effect of the herbicide on cMoat gene expression was studied. A 3.6-fold increase in cMoat mRNA levels and a 2.5-fold increase in cMoat protein content were observed in the liver of mice fed on a diet supplemented with 0.125% 2,4,5-T. These effects were due to an increased rate of gene transcription (3.9-fold) and were not associated with peroxisome proliferation. Significant increases in bile flow (2.23±0.39 versus 1.13±0.15 μl/min per g of liver; P < 0.05) and biliary GSH output (7.40±3.30 versus 2.65±0.34 nmol/min per g of liver; P < 0.05) were observed in treated animals. The hepatocellular concentration of total glutathione also increased in hepatocytes of treated mice (10.95±0.84 versus 5.12±0.47 mM; P < 0.05), because of the induction (2.4-fold) of the heavy subunit of the γ-glutamylcysteine synthetase (GCS-HS) gene. This is the first model of co-induction of cMoat and GCS-HS genes in vivo in the mouse liver, associated with increased glutathione synthesis and biliary glutathione output. Our observations are consistent with the hypothesis that the cMoat transporter plays a crucial role in the secretion of biliary GSH.

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“…Several investigators have recently reported that hyperbilirubinemia in EHBRs decreases the biliary secretion of various organic anions by impairing the canalicular membrane transport (26,28) and that the canalicular membrane vesicles isolated from EHBRs and TR Ϫ rats lack the ATP-dependent canalicular transport capability of organic anions (6,9). These observations suggest that the biliary secretory characteristics of organic anions in EHBRs closely resemble those in TR Ϫ and GY rats (6,26,28) and in humans with Dubin-Johnson syndrome (4). Thus, EHBRs can be used as an animal model for studying hyperbilirubinemia in humans.…”

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confidence: 67%

Biliary and renal excretions of cefpiramide in Eisai hyperbilirubinemic rats

Muraoka

Hasegawa

Nadai

et al. 1995

Antimicrob Agents Chemother

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Eisai hyperbilirubinemic mutant rats (EHBRs) with conjugated hyperbilirubinemia were recently derived from Sprague-Dawley rats (SDRs). The pharmacokinetic characteristics of the ␤-lactam antibiotic cefpiramide (CPM), which is mainly excreted into bile, were investigated in 10-and 20-week-old EHBRs and were compared with those in 20-week-old healthy SDRs. The pharmacokinetic parameters of CPM after an intravenous administration of 20 mg/kg of body weight were estimated for each rat by noncompartmental methods. When compared with age-matched healthy SDRs, significant decreases (by approximately 30%) in the systemic clearance of CPM were observed in 20-week-old EHBRs. The biliary clearance of CPM in 20-week-old EHBRs markedly decreased to less than 10% of that in age-matched healthy SDRs, while total urinary recovery of unchanged CPM increased to threefold and renal clearance doubled. However, no significant differences in any of the pharmacokinetic parameters of CPM were observed between the two groups of EHBRs. There were no significant differences among the three groups in the steady-state volume of distribution of CPM. The present study indicates that hyperbilirubinemia induces an increase in the urinary excretion ability of CPM in return for a reduction in the biliary excretion.Hyperbilirubinemia in rats is known to modify the pharmacokinetics of certain drugs as a result of the impairment of the process of biliary excretion (13,25,26,30). Hyperbilirubinemic mutant TR Ϫ and GY rats derived from Wistar strain rats have generally been used as experimental animal models for hyperbilirubinemia because they exhibit abnormalities in the biliary excretion of various organic anions and glucuronided and sulfated bile acids, which are similar to the symptoms of DubinJohnson syndrome in humans (8,11,16,24).Eisai hyperbilirubinemic mutant rats (EHBRs), which possess much higher concentrations of conjugated bilirubin in plasma, were derived from Sprague-Dawley rats (SDRs) (7,19). Several investigators have recently reported that hyperbilirubinemia in EHBRs decreases the biliary secretion of various organic anions by impairing the canalicular membrane transport (26,28) and that the canalicular membrane vesicles isolated from EHBRs and TR Ϫ rats lack the ATP-dependent canalicular transport capability of organic anions (6, 9). These observations suggest that the biliary secretory characteristics of organic anions in EHBRs closely resemble those in TR Ϫ and GY rats (6,26,28) and in humans with Dubin-Johnson syndrome (4). Thus, EHBRs can be used as an animal model for studying hyperbilirubinemia in humans.Cefpiramide (CPM), an anionic ␤-lactam antibiotic, exhibits antibacterial activity against gram-positive and gram-negative bacteria, in particular, to Pseudomonas aeruginosa, which is resistant to several antibiotics. CPM has been shown to be eliminated mainly into the bile in unchanged form by active biliary secretion in both humans and animals (18,22,31), suggesting that CPM could be prescribed as the preferred drug for the ...

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Chronic Idiopathic Jaundice With Unidentified Pigment in Liver Cells

Cited by 410 publications

References 0 publications

Characterization of Transport Protein Expression in Multidrug Resistance-Associated Protein (Mrp) 2-Deficient Rats

Characterization of Transport Protein Expression in Multidrug Resistance-Associated Protein (Mrp) 2-Deficient Rats

Induction of the multispecific organic anion transporter (cMoat/mrp2) gene and biliary glutathione secretion by the herbicide 2,4,5-trichlorophenoxyacetic acid in the mouse liver

Biliary and renal excretions of cefpiramide in Eisai hyperbilirubinemic rats

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