Abstract
The function of multidrug resistance-associated protein 2 (Mrp2) in the intestine and liver, as well as intestinal Mrp2 expression, was analyzed in CCl(4)-induced acute hepatic failure rats with hyperbilirubinemia. The plasma level of bilirubin glucuronides, endogenous Mrp2-substrates, was 26 microM at 24 h after CCl(4) treatment. Mrp2 protein levels in jejunum decreased to 41% of control level. Mrp2-mediated efflux of 2,4-dinitrophenyl-S-glutathione (DNP-GSH), an Mrp2-substrate, in jejunum decreased to 31% of control in vitro, and was almost completely suppressed in vivo to the same level as that in the presence of probenecid, an Mrp2-inhibitor. Biliary excretion of DNP-GSH was suppressed to the same level as that inhibited by intravenous probenecid. The suppression of Mrp2 and the increased plasma bilirubin glucuronides recovered within 24 h thereafter. These results suggest that hyperbilirubinemia in disease states may be related to the systemic suppression of Mrp2 function.
MeSH terms
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ATP-Binding Cassette Transporters / antagonists & inhibitors
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ATP-Binding Cassette Transporters / metabolism*
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Adenosine Triphosphate / metabolism
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Animals
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Area Under Curve
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Bile / metabolism
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Bilirubin / analogs & derivatives
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Bilirubin / blood
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Carbon Tetrachloride
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Dinitrochlorobenzene / metabolism
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Glutathione / analogs & derivatives
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Glutathione / pharmacokinetics
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Glutathione Transferase / metabolism
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Hyperbilirubinemia / blood
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Hyperbilirubinemia / chemically induced
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Hyperbilirubinemia / metabolism*
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Hyperbilirubinemia / pathology
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Ileum / metabolism
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Intestinal Mucosa / metabolism*
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Intestines / drug effects
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Intestines / pathology
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Jejunum / drug effects
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Jejunum / metabolism
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Liver / drug effects
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Liver / metabolism*
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Liver / pathology
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Liver Failure, Acute / blood
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Liver Failure, Acute / chemically induced
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Liver Failure, Acute / metabolism*
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Liver Failure, Acute / pathology
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Male
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Organ Size
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Probenecid / pharmacology
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Rats
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Rats, Sprague-Dawley
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Time Factors
Substances
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ATP-Binding Cassette Transporters
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Abcc2 protein, rat
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Dinitrochlorobenzene
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S-(2,4-dinitrophenyl)glutathione
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bilirubin glucuronate
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Adenosine Triphosphate
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Carbon Tetrachloride
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Glutathione Transferase
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Glutathione
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Probenecid
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Bilirubin