Up-regulation of multidrug resistance-associated protein 2 (MRP2) expression in rat hepatocytes by dexamethasone.
Regulation of multidrug resistance-associated protein (MRP2) expression in response to dexamethasone (DEX) was analyzed using mainly primary rat hepatocytes. Enhanced levels of MRP2 mRNAs associated with increased amounts of a 190 kDa MRP2 were found in cultured DEX-treated hepatocytes; similarly, administration of DEX to rats (100 mg/kg, i.p.) led to a marked increase of hepatic amounts of MRP2 mRNAs. Maximal induction of MRP2 expression in DEX-treated primary hepatocytes was reached with 10(-5) M DEX, a concentration higher than that (10(-7) M) required for maximal up-regulation of tyrosine aminotransferase (TAT), a typical glucocorticoid receptor-regulated enzyme. In addition, the anti-glucocorticoid compound RU486 failed to inhibit MRP2 induction caused by DEX whereas it fully blocked that of TAT. These findings therefore demonstrate that DEX is a potent inducer of MRP2 expression in rat hepatocytes through a mechanism that seems not to involve the classical glucocorticoid receptor pathway.
Courtois
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A
INSERM U456 Détoxication et Réparation Tissulaire', Faculté de Pharmacie, 2 Avenue du Pr. L. Bernard, 35043, Rennes, France.
Payen
L
L
Guillouzo
A
A
Fardel
O
O
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D024101:Mitochondrial Proteins; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012269:Ribosomal Proteins / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D013997:Time Factors; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; D006727:Hormone Antagonists; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D015735:Mifepristone; D003907:Dexamethasone