Dexamethasone- and osmolarity-dependent expression of the multidrug-resistance protein 2 in cultured rat hepatocytes.
Expression of the conjugate export pump multidrug-resistance protein 2 (MRP2) in liver is regulated by endotoxin and anti-tumour agents. This paper reports on the effects of dexamethasone and osmolarity on MRP2 expression. MRP2 expression was studied at the protein, mRNA, immunocytochemical and functional levels in cultured rat hepatocytes. Protein and mRNA expression of MRP2 in rat hepatocytes 24 and 48 h after isolation were largely dependent on the presence of dexamethasone (100 nmol/l) in the culture medium. MRP2 was localized at the pseudocanalicular membrane and increased expression of MRP2 was accompanied by a widening of the pseudocanaliculi. In presence of dexamethasone, hypo-osmolarity (205 mosmol/l) led to a strong induction of MRP2 mRNA and protein, whereas expression was decreased by hyperosmolarity (405 mosmol/l). Also, a decay of MRP2 protein and mRNA following dexamethasone withdrawal was osmosensitive. Expression of dipeptidylpeptidase IV, another canalicular protein, was unaffected by dexamethasone and osmolarity. It is concluded that glucocorticoids are strong inducers of MRP2 in liver. Besides short-term carrier insertion/retrieval, osmoregulation of MRP2 also involves a long-term effect on MRP2 expression.
Kubitz
R
R
Medizinische Universitätsklinik, Heinrich Heine Universität Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Warskulat
U
U
Schmitt
M
M
Häussinger
D
D
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001648:Bile Canaliculi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D009994:Osmolar Concentration; D010750:Phosphoproteins / Q000032:analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D062826:Zonula Occludens-1 Protein
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D008565:Membrane Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D003907:Dexamethasone; C095122:multidrug resistance protein 3; D018819:Dipeptidyl Peptidase 4