Function of multidrug resistance-associated protein 2 in acute hepatic failure rats.
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.
Yokooji
Tomoharu
T
Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Hiroshima 734-8551, Japan.
Murakami
Teruo
T
Yumoto
Ryoko
R
Nagai
Junya
J
Takano
Mikihisa
M
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001663:Bilirubin / Q000031:analogs & derivatives / Q000097:blood; D002251:Carbon Tetrachloride; D004137:Dinitrochlorobenzene / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005982:Glutathione Transferase / Q000378:metabolism; D006932:Hyperbilirubinemia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007082:Ileum / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009929:Organ Size; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D004137:Dinitrochlorobenzene; C030190:S-(2,4-dinitrophenyl)glutathione; C016266:bilirubin glucuronate; D000255:Adenosine Triphosphate; D002251:Carbon Tetrachloride; D005982:Glutathione Transferase; D005978:Glutathione; D011339:Probenecid; D001663:Bilirubin