Environmental Health and Occupational Medicine Center, Department of Pharmacology, Toxicology, and Therapeutics, 3901 Rainbow Boulevard, University of Kansas Medical Center, Kansas City, Kansas 66160-7417
Received November 5, 2001; accepted February 8, 2002
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ABSTRACT |
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Key Words: aryl hydrocarbon receptor (AhR); antioxidant/electrophile-response element (ARE/EpRE); branched DNA (bDNA); constitutive androstane receptor (CAR); cytochrome P450 (CYP); multidrug resistance protein 2 (Mrp2); peroxisomal proliferator-activating receptor- (PPAR
); pregnane-X receptor (PXR).
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INTRODUCTION |
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Therefore, the purpose of this study was 2-fold: first, to comprehensively analyze the effects of 18 prototypical microsomal enzyme inducers on rat Mrp2 protein expression, and second, to determine whether the effects of microsomal enzyme inducers on Mrp2 protein were due to the upregulation of Mrp2 mRNA expression. Furthermore, the data will provide essential information as to whether classes of microsomal enzyme inducers affect rat Mrp2 expression in similar manners, thus implicating the potential roles of specific ligand-activated transcription factor pathways. Microsomal enzyme inducers were divided according to the following classes of transcription factor ligands/CYP inducers (Fig. 1): AhR ligands/CYP1A inducers (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], indole-3-carbinol [I-3-C], ß-naphthoflavone [BNF], and 3,3`4,4`,5-pentachlorobiphenyl [PCB 126]), constitutive androstane receptor (CAR) ligands/CYP2B inducers (phenobarbital [PB], 2,2`,4,4`,5-pentachlorobiphenyl [PCB 99], and diallyl sulfide [DAS]), pregnane-x receptor (PXR) ligands/CYP3A inducers (pregnenolone-16
-carbonitrile [PCN], spironolactone [SP], and dexamethasone [DEX]), peroxisomal proliferator-activating receptor-
(PPAR
) ligands/CYP4A inducers (clofibric acid [CLOF], di-(2-ethylhexyl)phthalate [DEHP], and perfluorodecanoic acid [PFDA]), antioxidant/electrophile response element (ARE/EpRE) ligands (ethoxyquin [EQ] and oltipraz [OPZ]), and CYP2E1 inducers (isoniazid [INH], acetylsalicylic acid [ASA], and streptozotocin [STZ]). Results from this study indicate that rat Mrp2 protein is significantly increased by PXR and ARE/EpRE ligands, and PPAR
ligands tend to decrease Mrp2 protein. In contrast, rat Mrp2 mRNA expression is not significantly affected by any microsomal enzyme inducer used in this study, thus suggesting that rat Mrp2 protein is increased by posttranscriptional modifications that are regulated by PXR and ARE/EpRE ligands.
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MATERIALS AND METHODS |
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Treatment of rats with microsomal enzyme inducers.
Male Sprague-Dawley rats (Sasco, Kingston, NY) were housed at 250C with a 12-h light-dark cycle according to AAALAC guidelines. Rats received water and food ad libitum, and were allowed to acclimate to their environment for 5 days before the study began. Rats (225 g) were subjected to the following microsomal enzyme-inducing chemicals: TCDD (3.9 µg/kg, corn oil, ip, 1 day), I-3-C (56 mg/kg, corn oil, po), BNF (100 mg/kg, corn oil, ip), PCB 126 (40 µg/kg, corn oil, po, 7 days), PB (80 mg/kg, saline, ip), PCB 99 (16 mg/kg, corn oil, po, 7 days), DAS (500 mg/kg, corn oil, ip), PCN (50 mg/kg, corn oil, ip), SP (75 mg/kg, corn oil, ip), DEX (50 mg/kg, corn oil, ip), CLOF (200 mg/kg, saline, pH 7, ip), DEHP (1200 mg/kg, corn oil, po), PFDA (40 mg/kg, corn oil, ip, 1 day), EQ (150 mg/kg, corn oil, po), OPZ (150 mg/kg, corn oil, po), INH (200 mg/kg, saline, ip), ASA (500 mg/kg, corn oil, po), STZ (100 mg/kg, 100 mM sodium citrate, pH 4.5, ip, 1 day), corn oil (ip), corn oil (po), and saline (ip). All animals were treated for 4 days unless otherwise noted, and injections were in a volume of 5 ml/kg. On day 5, livers were removed, snap frozen in liquid nitrogen, and stored at 800C.
Total membrane protein preparation.
Liver protein samples were prepared as previously described (Johnson et al., 2002). Protein concentrations were determined using a bicinchoninic acid (BCA) assay kit (Pierce, Rockford, IL).
Western blot analysis.
Protein samples (30 µg/well) were mixed with sample buffer, loaded onto a 7.5% SDS-polyacrylamide gel, and run electrophoretically on a Western blot apparatus (Gibco BRL, Gaithersburg, MD). Protein samples were not boiled prior to loading. Each gel contained a loading control that served as a basis for internal comparison. Protein was transferred overnight to nitrocellulose membranes (Novex, San Diego, CA). Membranes were blocked with 5% nonfat dry milk in Tris-buffered saline with 0.1% Tween 20 (TBS/T). The membranes were then incubated overnight at 40C with a 1:4000 dilution of anti-Mrp2 primary antibody EAG15 (generated in our laboratory according to Buchler et al., 1996) in 1% nonfat dry milk in TBS/T. Membranes were washed with TBS/T and then incubated at room temperature with donkey, antirabbit IgG-horseradish peroxidase-linked secondary antibody (Amersham, Arlington Heights, IL), diluted in TBS/T containing 1% nonfat dry milk. Mrp2 protein was detected using an enhanced chemiluminescence (ECLTM) kit (Amersham).
Isolation of total RNA.
Total RNA was isolated using RNAzol B reagent (Tel-Test Inc., Friendswood, TX) as per the manufacturer's protocol. Each RNA pellet was resuspended in 0.2 ml DEPC-treated water. The concentration of total RNA in each sample was quantified spectrophotometrically at 260 nm. The integrity of each RNA sample was analyzed by formaldehyde-agarose (1.2% agarose, 2.1 M formaldehyde in 1X MOPS) gel electrophoresis.
Quantigene TM branched DNA (bDNA) signal amplification assay.
Probe sets for detection of all CYPs (CYP1A1, CYP2B1/2, CYP3A1/23, CYP4A2/3, & CYP2E1) and QR, as well as Mrp2-specific oligonucleotide probes, have been previously described (Hartley and Klaassen, 2000; Johnson et al., 2002). CYP, QOR, and Mrp2-specific oligonucleotide probe sets (i.e., blocker probes, capture probes, and label probes) were combined and diluted to 50 fmol/µl in the lysis buffer supplied in the QuantigeneTM bDNA Signal Amplification Kit (Bayer Diagnostics, East Walpole, MA). The bDNA assay was run as previously described (Johnson et al., 2002). The enzymatic reaction was allowed to proceed for 30 min at 370C, and luminescence was measured with the QuantiplexTM 320 bDNA Luminometer (Bayer Diagnostics) interfaced with QuantiplexTM Data Management Software Version 5.02 (Bayer Diagnostics) for analysis of luminescence from 96-well plates.
Statistics.
All results were analyzed statistically by one-way ANOVA, followed by Duncan's multiple range post hoc test. Statistically significant results (p < 0.05) are denoted by an asterisk (*).
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RESULTS |
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DISCUSSION |
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All 3 CYP3A inducers significantly increased Mrp2 protein expression; PCN, SP, and DEX increased Mrp2 protein expression approximately 340, 230, and 520%, respectively, above control (Fig. 3). The inductive effects of PXR ligands on Mrp2 protein expression correspond with what is known about their inductive effects on biliary excretion of organic anions, such as GSH, DBSP, GS-BSP, and bilirubin (Faed et al., 1984
; Klaassen, 1970
; Madhu et al., 1993
; Morisoli et al., 1982
; Pellegrino et al., 1982
; Zsigmond and Solymoss, 1972
). In contrast to Mrp2 protein, none of the PXR ligands/CYP3A inducers significantly upregulated Mrp2 mRNA expression (Fig. 4
). PXR ligands/CYP3A inducers produce a unique phenomenon in that all 3 inducers significantly increase Mrp2 protein expression without significantly affecting Mrp2 mRNA expression. Furthermore, PCN increases Mrp2 protein, but not Mrp2 mRNA, in a time-dependent manner, so up regulation of Mrp2 mRNA at earlier time points was not overlooked (Johnson et al., 2002). Thus, the CYP3A inducers used in this experimentall of which were rat PXR ligands (Jones et al., 2000
)appear to increase Mrp2 protein expression by a PXR-mediated posttranscriptional mechanism.
There appears to be a discrepancy between the effects of CYP3A4 inducers/PXR ligands on Mrp2 expression in vitro and in vivo. Previous studies have demonstrated that both human and rodent CYP3A4 inducers upregulate human MRP2 and rodent Mrp2 mRNA expression, respectively, through PXR (also called SXR in humans) (Courtois et al., 1999a; Dussault et al., 2001
; Kast et al., 2001
). Yet the regulation of Mrp2 by CYP3A4 inducers/PXR ligands appears to be more complex in vivo. In rhesus monkeys, rifampicin, a human PXR ligand, upregulates MRP2 mRNA, but has almost no effect on MRP2 protein (Kauffmann et al., 1998
). Similarly, this study demonstrated that PXR ligands induce Mrp2 protein, but not Mrp2 mRNA. The differences between in vitro and in vivo induction of Mrp2 expression may be due to the delivery of drug to the target organ. Cell culture allows measurement of effects of chemicals at specific concentrations on target cells, yet in vivo studies also must take into account the complex disposition of chemicals in the body in addition to the effects of chemicals on the target cells. Therefore, target cells may not be exposed to the complete dosage of chemical due to systemic uptake and clearance of chemicals from the body. Thus, CYP3A4 inducers/PXR ligands may directly upregulate rat Mrp2 mRNA expression in cell culture, but in whole animals, rat Mrp2 protein is induced not by the PXR-mediated activation of the Mrp2 gene, but by a PXR-mediated posttranscriptional mechanism.
ARE/EpRE ligands also significantly induced Mrp2 expression. Both EQ and OPZ significantly increased Mrp2 protein approximately 200% and 270%, respectively, above control (Fig. 3). This data complements studies in which quercetin and t-butylhydroquinone (tBHQ), two additional ARE/EpRE ligands, induce Mrp2 protein expression in Caco-2 cells (Bock et al., 2000
). Both EQ and OPZ tended to also upregulate Mrp2 mRNA (approximately 40 and 80% above control, respectively), though neither were statistically significant (Fig. 4
). Therefore, ARE/EpRE ligands increase Mrp2 protein expression, but not Mrp2 mRNA expression, and that the increase in Mrp2 protein by EQ and OPZ may be largely due to an ARE/EpRE-mediated mechanism independent of the Mrp2 gene. This is supported by the fact that no ARE/EpRE consensus site has yet been found in the rat Mrp2 gene promoter (Kauffmann and Schrenk, 1998
). An apparent discrepancy exists between the data from this experiment and a study by Courtois et al. (1999b) in which OPZ did not increase Mrp2 protein when administered to rats in the diet (0.075% (w/w)). The differences may be attributed to the smaller dosage of OPZ ingested by the rats when administered in feed versus a higher dosage when administered by gavage. Thus, higher concentrations of OPZ may be needed to increase Mrp2 protein in vivo, as seen in this study.
Another surprising finding was the relative inability of PB and other CYP2B inducers/CAR ligands to significantly affect Mrp2 expression. PB increases biliary excretion of numerous organic anions that are substrates of Mrp2 (Faed et al., 1984; Klaassen, 1970
; Madhu et al., 1993
; Morisoli et al., 1982
; Pellegrino et al., 1982
; Zsigmond and Solymoss, 1972
) and a previous report demonstrates that PB also significantly increases Mrp2 protein (Johnson et al., 2002). Yet, this study and others have shown that PB has only mild inductive effects on Mrp2 expression (Hagenbuch et al., 2001
; Ogawa et al., 2000
), most likely due to the CAR-mediated activation of the ER8 response element in the Mrp2 gene promoter (Kast et al., 2001
). Perhaps this modest increase in Mrp2 protein expression by CYP2B inducers/CAR ligands is enough to have significant effects on Mrp2 function. An alternative postulation is that PB and other CYP2B inducers/CAR ligands primarily induce other canalicular transporters that have the same organic anion substrates as Mrp2 (Jansen et al., 1987 Jansen et al., 1993; Johnson and Klaassen, 2002
; Kurisu et al., 1991; Sathirakul et al., 1993), thus explaining the increase in organic anion elimination into bile. In contrast, PB can also decrease biliary excretion of organic anions (Gregus et al., 1990
; Studenberg and Brouwer, 1992
; Watkins and Klaassen, 1982
). Recently, Cherrington et al. (2002) demonstrated that PB and other CAR ligands upregulate mRNA of multidrug resistance protein 3 (Mrp3), a sinusoidal transporter protein that is a member of the MRP subfamily of transporters. Because Mrp2 and Mrp3 share similar substrates, it is possible that the increased Mrp3 results in higher sinusoidal efflux and lower biliary efflux of organic anions.
Other classes of enzyme inducers used in this experiment did not significantly affect Mrp2 protein expression, and, more importantly, the inducer within these other classes did not exhibit related effects on Mrp2 protein expression. A notable exception was the class of CYP4A inducers/PPAR ligands. Though not statistically significant, all 3 CYP4A inducers/PPAR
ligands tended to decrease Mrp2 protein approximately 60% below control (Fig. 3
). This was supported by the fact that CLOF decreases biliary excretion of GS-BSP, an Mrp2 substrate (James and Ahokas, 1992
). In addition to Mrp2 protein, none of these other inducer classes significantly affected Mrp2 mRNA expression, nor did the inducers within the other classes exhibit related effects on Mrp2 mRNA expression. Therefore, the data in this study suggest that the AhR, CAR, and PPAR
are not molecular mechanisms by which microsomal enzyme inducers affect Mrp2 expression in vivo. This conclusion is supported by the findings that the xenobiotic response element (XRE), the CAR response element (PBREM), and the PPAR response element (PPRE) are either absent or nonfunctional in the 5`-flanking region of the rat Mrp2 gene (Denson et al., 2000
; Kauffmann and Schrenk, 1998
).
In summary, PXR ligands/CYP3A inducers (PCN, SP, and DEX) and ARE/EpRE ligands (EQ and OPZ) significantly increase Mrp2 protein. CYP4A inducers (CLOF, DEHP, and PFDA), however, tend to decrease Mrp2 protein, though not significantly. In contrast to Mrp2 protein, none of the microsomal enzyme inducers affect Mrp2 mRNA, though ARE/EpRE ligands (EQ and OPZ) tended to upregulate Mrp2 mRNA. Thus, PXR, PPAR, and ARE/EpRE ligands appear to regulate Mrp2 protein expression by posttranscriptional mechanisms. This conclusion appears at odds with the current dogma of transcriptional upregulation being the main mechanism by which drug-metabolizing enzyme inducers increase CYPs. Yet, several studies demonstrate that Mrp2 protein expression does not always correlate with Mrp2 mRNA expression in rat. For example, rat Mrp2 protein expression does not correspond with Mrp2 mRNA expression along the intestinal tract (Mottino et al., 2000
), but, more importantly, intestinal excretion of dinitrophenol-glutathione (GS-DNP), an Mrp2 substrate, corresponds best with Mrp2 protein expression, and not Mrp2 mRNA expression, along the intestinal tract (Gotoh et al., 2000
). In addition, differences between rat Mrp2 protein and mRNA expression have been noted in other studies ranging from pathological events, such as liver regeneration (Gerloff et al., 1999
) and extrahepatic cholestasis (Paulusma et al., 2000
), to chemical treatment, such as ethinyl estradiol (Trauner et al., 1997
). Therefore, it is likely that the regulation of rat Mrp2 protein expression in vivo occurs in a nontraditional manner, i.e., not by transcriptional upregulation but by posttranscriptional mechanisms. The data from this study also indicate that the measurement of rat Mrp2 mRNA after microsomal enzyme induction is not an adequate indication of Mrp2 protein expression and function. Therefore, additional protein screening technologies should be employed in order to adequately assess the effects of chemicals on Mrp2 protein expression and function.
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ACKNOWLEDGMENTS |
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NOTES |
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2 To whom correspondence should be addressed. Fax: (913) 588-7501. Email: cklaasse{at}kumc.edu.
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REFERENCES |
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---|
Buchler, M., Konig, J., Brom, M., Kartenbeck, J., Spring, H., Horie, T., and Keppler, D. (1996). cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. J. Biol. Chem. 271, 1509115098.
Buetler, T. M., Bammler, T. K., Hayes, J. D., and Eaton, D. L. (1996). Oltipraz-mediated changes in aflatoxin B(1) biotransformation in rat liver: Implications for human chemointervention. Cancer Res. 56, 23062313.[Abstract]
Buetler, T. M., Gallagher, E. P., Wang, C., Stahl, D. L., Hayes, J. D., and Eaton, D. L. (1995). Induction of phase I and phase II drug-metabolizing enzyme mRNA, protein, and activity by BHA, ethoxyquin, and oltipraz. Toxicol. Appl. Pharmacol. 135, 4557.[ISI][Medline]
Cherrington, N. J., Hartley, D. P., Li, N., Johnson, D. R., and Klaassen, C. D. (2002). Organ distribution of multidrug resistance proteins 1, 2, and 3 (Mrp1, 2, and 3) mRNA and hepatic induction of Mrp3 by constitutive androstane receptor activators in rats. J. Pharmacol. Exp. Ther. 300, 97104.
Courtois, A., Payen, L., Guillouzo, A., and Fardel, O. (1999a). Upregulation of multidrug resistance-associated protein 2 (Mrp2) expression in rat hepatocytes by dexamethasone. FEBS Lett. 459, 381385.[ISI][Medline]
Courtois, A., Payen, L., Vernhet, L., Morel, F., Guillouzo, A., and Fardel, O. (1999b). Differential regulation of canalicular multispecific organic anion transporter (cMOAT) expression by the chemopreventive agent oltipraz in primary rat hepatocytes and in rat liver. Carcinogenesis 20, 23272330.
Damme, B., Darmer, D., and Pankow, D. (1996). Induction of hepatic cytochrome P4502E1 in rats by acetylsalicylic acid or sodium salicylate. Toxicology 106, 99103.[ISI][Medline]
Denson, L. A., Auld, K. L., Schiek, D. S., McClure, M. H., Mangelsdorf, D. J., and Karpen, S. J. (2000). Interleukin-1ß suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation. J. Biol. Chem. 275, 88358843.
Dussault, I., Lin, M., Hollister, K., Wang, F. H., Synold, T. W., and Forman, B. M. (2001). Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR. J. Biol. Chem. 276, 3330933312.
Faed, E. M., Dobbs, B. R., and Lee, D. (1984). Glucuronidation and elimination of diflunisal in the isolated perfused rat liver: Effect of pretreatment with phenobarbitone, clofibric acid, and spironolactone. Arch. Int. Pharmacodyn. Ther. 272, 416.[ISI][Medline]
Gant, T. W., Silverman, J. A., and Thorgeirsson, S. S. (1992). Regulation of P-glycoprotein gene expression in hepatic cultures and liver cell lines by a trans-acting transcriptional repressor. Nucleic Acids Res. 20, 28412846.[Abstract]
Geick, A., Eichelbaum, M., and Burk, O. (2001). Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem. 276, 1458114587.
Gerloff, T., Geier, A., Steiger, B., Hagenbuch, B., Meier, P. J., Matern, S., and Gartung, C. (1999). Differential expression of basolateral and canalicular organic anion transporters during regeneration of rat liver. Gastroenterology 117, 14081415.[ISI][Medline]
Gotoh, Y., Suzuki, H., Kinoshita, S., Hirohashi, T., Kato, Y., and Sugiyama, Y. (2000). Involvement of an organic anion transporter (canalicular multispecific organic anion transporter/multidrug resistance-associated protein 2) in gastrointestinal secretion of glutathione conjugates in rats. J. Pharmacol. Exp. Ther. 292, 433439.
Gregus, Z., Madhu, C., and Klaassen, C. D. (1990). Effect of microsomal enzyme inducers on biliary and urinary excretion of acetaminophen metabolites in rats. Decreased hepatobiliary and increased hepatovascular transport of acetaminophen-glucuronide after microsomal enzyme induction. Drug Metab. Dispos. 18, 1019.[Abstract]
Guo, G. L., Choudhuri, S., and Klaassen, C. D. (2002) Induction profile of rat organic anion transporting polypeptide 2 (oatp2) by prototypical drug-metabolizing enzyme inducers that activate gene expression through ligand-activated transcription factor pathways. J. Pharmacol. Exp. Ther. 300, 206212.
Hagenbuch, N., Reichel, C., Stieger, B., Cattori, V., Fattinger, K. E., Landmann, L., Meier, P. J., and Kullak-Ublick, G. A. (2001). Effect of phenobarbital on the expression of bile salt and organic anion transporters of rat liver. J. Hepatol. 34, 881887.[ISI][Medline]
Hartley, D. P., and Klaassen, C. D. (2000). Detection of chemical-induced differential expression of rat hepatic cytochrome P450 mRNA transcripts using branched DNA signal amplification technology. Drug Metab. Dispos. 28, 608616.
James, S. I., and Ahokas, J. T. (1992). Effect of peroxisome proliferators on glutathione-dependent sulphobromophthalein excretion. Xenobiotica 22, 14251432.[ISI][Medline]
Javitt, N. B., Kondo, T., and Kuchiba, K. (1978). Bile acid secretion in Dubin-Johnson syndrome. Gastroenterology 75, 931932.[ISI][Medline]
Johnson, D. R., Habeebu, S. S. M., and Klaassen, C. D. Increase in bile flow and biliary excretion of glutathione-derived sulfhydryls in rats by drug-metabolizing enzyme inducers are mediated by multidrug resistance protein 2. Toxicol Sci. 66, 1626.
Johnson, D. R., and Klaassen, C. D. (2002). Role of rat multidrug resistance protein 2 in plasma and biliary disposition of dibromosulfobromophthalein after microsomal enzyme induction. Toxicol. Appl. Pharmacol. 180, 5663.[ISI][Medline]
Jones, S. A., Moore, L. B., Shenk, J. L., Wisely, G. B., Hamilton, G. A., McKee, D. D., Tomkinson, N. C., LeCluyse, E. L., Lambert, M. H., Willson. T. M., Kliewer, S. A., and Moore, J. T. (2000). The pregnane-X receptor: A promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol. 14, 2739.
Kast, H. R., Goodwin, B., Tarr, P. T., Jones, S. A., Anisfeld, A. M., Stoltz, C. M., Tontonoz, P., Kliewer, S., Willson, T. M., and Edwards, P. A. (2001). Regulation or multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane-X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J. Biol. Chem. 277, 29082915.[Medline]
Kauffmann, H. M., Keppler, D., Gant, T. W., and Schrenk. D. (1998). Induction of hepatic mrp2 (cmrp/cmoat) gene expression in nonhuman primates treated with rifampicin or tamoxifen. Arch. Toxicol. 72, 763768.[ISI][Medline]
Kauffmann, H. M., and Schrenk, D. (1998). Sequence analysis and functional characterization of the 5`-flanking region of the rat multidrug resistance protein 2 (mrp2) gene. Biochem. Biophys. Res. Commun. 245, 325331.[ISI][Medline]
Klaassen, C. D. (1970). Plasma disappearance and biliary excretion of sulfobromophthalein and phenol-3,6-dibromphthalein disulfonate after microsomal enzyme induction. Biochem. Pharmacol. 19, 12411249.[ISI][Medline]
Madhu, C., Mitchell, D. Y., and Klaassen, C. D. (1993). Effect of P-450 inducers on biliary excretion of glutathione and its hydrolysis products. Correlation between hepatic -glutamyltranspeptidase activity and the proportion of glutathione hydrolysis products in bile. Drug Metab. Dispos. 21, 342349.[Abstract]
Morisoli, L. S., Mottino, A. D., Pellegrino, J. M., Guibert, E. E., and Rodriguez-Garay, E. A. (1982). Effect of spironolactone on bilirubin metabolism in rat liver and small intestinal mucosa. Biochem. Pharmacol. 31, 14691474.[ISI][Medline]
Mottino, A. D., Hoffman, T., Jennes, L., and Vore, M. (2000). Expression and localization of multidrug-resistant protein mrp2 in rat small intestine. J. Pharmacol. Exp. Ther. 293, 717723.
Ogawa, K., Suzuki, H., Hirohashi, T., Ishikawa, T., Meier, P. J., Hirose, K., Akizawa, T., Yoshioka, M., and Sugiyama, Y. (2000). Characterization of inducible nature of MRP3 in rat liver. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G438446.
Oude-Elferink, R. P., and Jansen, P. L. (1994). The role of the canalicular multispecific organic anion transporter in the disposal of endo- and xenobiotics. Pharmacol. Ther. 64, 7797.[ISI][Medline]
Park, K. S., Sohn, D. H., Veech, R. L., and Song, B. J. (1993). Translational activation of ethanol-inducible cytochrome P450 (CYP2E1) by isoniazid. Eur. J. Pharmacol. 248, 714.[Medline]
Paulusma, C. C., Kool, M., Bosma, P. J., Scheffer, G. L., ter Borg, F., Scheper, R. J., Tytgat, G. N. J., Borst, P., Baas, F., and Oude-Elferink, P. J. (1997). A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 25, 15391542.[ISI][Medline]
Paulusma, C. C., Kothe, M. J., Bakker, C. T., Bosma, P. J., van Bokhoven, I., van Marle, J., Bolder, U., Tytgat, G. N., and Oude-Elferink, R. P. (2000). Zonal downregulation and redistribution of the multidrug resistance protein 2 during bile duct ligation in rat liver. Hepatology 31, 684693.[ISI][Medline]
Pellegrino, J. M., Mottino, A. D., Rodriguez, J. V., and Rodriguez-Garay, E. A. (1982). Biliary excretion of sulfobromophthalein in isolated perfused livers from normal and spironolactone-treated rats. Experientia 38, 112114.[ISI][Medline]
Rausch-Derra, L. C., Hartley, D. P., Meier, P. J., and Klaassen, C. D. (2001). Differential effects of microsomal enzyme-inducing chemicals on the hepatic expression of rat organic anion transporters, OATP1 and OATP2. Hepatology 33, 14691478.[ISI][Medline]
Sonderfan, A. J., and Parkinson, A. (1988). Inhibition of steroid 5-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450. Arch. Biochem. Biophys. 265, 208218.[ISI][Medline]
Studenberg, S. D., and Brouwer, K. L. (1992). Impaired biliary excretion of acetaminophen glucuronide in the isolated perfused rat liver after acute phenobarbital treatment and in vivo Phenobarbital pretreatment. J. Pharmacol. Exp. Ther. 261, 10221027.[Abstract]
Trauner, M., Arrese, M., Soroka, C. J., Ananthanarayanan, M., Koeppel, T. A., Schlosser, S. F., Suchy, F. J., Keppler, D., and Boyer, J. L. (1997). The rat canalicular conjugate export pump (Mrp2) is downregulated in intrahepatic and obstructive cholestasis. Gastroenterology 113, 255264.[ISI][Medline]
Tsutsumi, M., Lasker, J. M., Takahashi, T., and Lieber, C. S. (1993). In vivo induction of hepatic P4502E1 by ethanol: Role of increased enzyme synthesis. Arch. Biochem. Biophys. 304, 209218.[ISI][Medline]
Vargas, M., Lamb, J. G., and Franklin, M. R. (1998). Phase-II selective induction of hepatic drug-metabolizing enzymes by oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione], 1,7-phenanthroline, and 2,2`-dipyridyl in rats is not accompanied by induction of intestinal enzymes. Drug Metab. Dispos. 26, 9197.
Watkins, J. B., and Klaassen, C. D. (1982). Effect of inducers and inhibitors on glucuronidation on the biliary excretion and choleretic action of valproic acid in the rat. J. Pharmacol. Exp. Ther. 220, 305310.[Abstract]
Wielandt, A. M., Vollrath, V., Manzano, M., Miranda, S., Accatino, L., and Chianale, J. (1999). Induction of the multispecific organic anion transporter (cMoat/mrp2) gene and biliary glutathione secretion by the herbicide 2, 4, 5-trichlorophenoxyacetic acid in the mouse liver. Biochem. J. 341, 105111.[ISI][Medline]
Wilson, C., and Safe, S. (1998). Mechanisms of ligand-induced aryl hydrocarbon receptor-mediated biochemical and toxic responses. Toxicol. Pathol. 26, 657671.[ISI][Medline]
Zsigmond, G., and Solymoss, B. (1972). Effect of spironolactone, pregnenolone-16-carbonitrile, and cortisol on the metabolism and biliary excretion of sulfobromophthalein and phenol-3,6-dibromophthalein disulfonate in rats. J. Pharmacol. Exp. Ther. 183, 499507.[ISI][Medline]