Differential regulation of multidrug resistance-associated protein 2 (MRP2) and cytochromes P450 2B1/2 and 3A1/2 in phenobarbital-treated hepatocytes.
Multidrug resistance-associated protein 2 (MRP2) is a drug efflux pump found at the biliary pole of hepatocytes. In the present study, we have investigated its expression in response to phenobarbital, a liver tumor promoter known to up-regulate hepatic cytochromes P450 (CYPs), such as CYP2B1/2 and CYP3A1/2. MRP2 mRNA and protein levels were found to be markedly increased in both primary rat and human hepatocytes exposed to phenobarbital. However, features of this up-regulation, especially the dose-response, were different from those of the induction of CYP2B1/2 and CYP3A1/2. In addition, hepatic MRP2 expression remained unaltered in rats treated by phenobarbital that, by contrast, increased CYP2B1/2 and CYP3A1/2 gene expression in the liver. Therefore, MRP2 and CYPs appeared differently regulated in response to phenobarbital in both in vivo and in vitro situations, suggesting that cellular and molecular mechanisms underlying up-regulation of MRP2 are, at least in part, unrelated to those operating for CYPs. Phenobarbital-related MRP2 induction in primary rat hepatocytes was associated with some phenotypic effects of the barbiturate, such as prolonged cell survival and inhibition of cell proliferation. Phenobarbital also inhibited growth of human hepatoma HepG(2) cells and increased their level of MRP2 gene expression. Such results may favor a putative relationship between phenobarbital-mediated MRP2 regulation in cultured liver parenchymal cells and alteration of cell cycle and survival.
Courtois
Arnaud
A
INSERM U456, Faculte de Pharmacie, 2 Avenue du Pr L Bernard, 35043, Rennes, France.
Payen
Lea
L
Le Ferrec
Eric
E
Scheffer
George L
GL
Trinquart
Yolande
Y
Guillouzo
Andre
A
Fardel
Olivier
O
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008297:Male; D024101:Mitochondrial Proteins; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012269:Ribosomal Proteins / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D013250:Steroid Hydroxylases / Q000378:metabolism
C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C025619:steroid 16-beta-hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; D010634:Phenobarbital