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SHORT COMMUNICATION

INDUCTION OF ABCC3 (MRP3) BY PREGNANE X RECEPTOR ACTIVATORS

	Abstract

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The pregnane X receptor (PXR) mediates the induction of various genes by xenobiotics, including several ATP-binding cassette transporters. PXR is also activated by bile acids likely to prevent their accumulation to toxic levels; however, the role of PXR in the regulation of MRP3, an important bile acid efflux transporter, has not been elucidated. The impact of PXR activators on the hepatic expression of MRP3 was examined in vivo and in vitro. The human hepatoma cell lines HuH7 and HepG2 were treated with PXR activators including clotrimazole, rifampicin, 17ß-hydroxy-11ß-[4-dimethylamino phenyl]-17-[1-propynyl]estra-4,9-dien-3-one (RU486), metyrapone, nifedipine, lithocholic acid, and 5-pregnen-3ß-ol-20-one-16-carbonitrile (PCN). Levels of MRP3 mRNA, as determined by reverse transcription-polymerase chain reaction, were induced 1.6- to 8-fold in a dose-dependent manner (p < 0.05). Corresponding decreases in the multidrug resistance-associated protein-dependent cellular retention of 5-carboxyfluorescein were also seen in the treated HuH7 cells. In vivo studies demonstrated increased PXR mRNA and induction of MRP3 mRNA in the livers of wild-type mice treated with the PXR activator RU486. On the other hand, MRP3 induction was not seen in the RU486-treated PXR-null mice. These results suggest that PXR activation may play a role in the regulation of MRP3 expression.

MRP3 is a basolateral efflux transporter that transports bile acids as well as several clinically important anionic drugs such as etoposide, methotrexate, and glucuronide conjugates. The expression of MRP3 in rat and human liver is low under normal conditions but is induced during cholestasis and in the absence of MRP2 or bile salt export pump (Konig et al., 1999; Donner and Keppler, 2001; Schuetz et al., 2001; Scheffer et al., 2002). Bile acids, in particular lithocholic acid, have been demonstrated to activate PXR likely as a mechanism to control their production and metabolism to prevent their accumulation to toxic levels (Staudinger et al., 2001; Xie et al., 2001). Because MRP3 is an important bile acid and drug transporter, the activation of PXR may also lead to MRP3 up-regulation as an additional cellular protective mechanism. However, the involvement of PXR in the regulation of MRP3 has not been reported.

Therefore, in this report we examined the impact of various PXR activators on the hepatic expression of MRP3 using a combination of in vitro and in vivo studies. Results from this study suggest that PXR activation induces the expression and activity of MRP3; thus, PXR activation plays a role in the regulation of MRP3.

	Materials and Methods

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The PXR activators rifampicin, clotrimazole, metyrapone, nifedipine, RU486, lithocholic acid, and 5-pregnen-3ß-ol-20-one-16-carbonitrile (PCN), as well as fetal bovine serum, indomethacin, 5-carboxyfluorescein diacetate, MTT, and Triton X-100 were purchased from Sigma-Aldrich Canada (Burlington, ON, Canada). Cell culture media, agarose, and trypsin were purchased from Invitrogen (Burlington, ON, Canada). PCR primers were synthesized by the DNA Synthesis Centre, Hospital for Sick Children (Toronto, ON, Canada). HepG2 cells were obtained from the American Type Culture Collection (Manassas, VA), and HuH7 cells were kindly donated by Dr. C. Richardson of the Ontario Cancer Institute (Toronto, ON, Canada).

HuH7 cells were maintained in Dulbecco's modified Eagle's medium, whereas HepG2 cells were maintained in -minimum essential medium. Both were supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin solution and were grown at 37°C with 5% CO₂. Medium was replaced twice per week, and cells were trypsinized and subcultured every 7 days.

In vitro mRNA studies were performed in 100-mm petri dishes. Once the cells reached confluency, they were treated with dimethyl sulfoxide vehicle control or various concentrations of PXR activators (ranging from 10 µM to 1 mM). The mRNA levels of MRP2, MRP3, MRP6, and PXR were determined at specified time points (6 to 48 h) by semiquantitative RT-PCR and were normalized to GAPDH as previously described (Lee and Piquette-Miller, 2001). PCR standard curves for each gene product were generated from serial dilutions of RT products, and the optimal amounts of template were determined from the linear portions of the resulting PCR calibration curves. Results from RT-PCR were routinely confirmed on Northern blots, and discrepancies were not observed. Primer sequences for PXR have been previously reported (Dotzlaw et al., 1999). Normalization of optical densities of bands to either 18S rRNA or GAPDH mRNA was found to give similar results.

Cells were seeded onto 6-well plates and treated with PXR activators (10-500 µM) for 24 and 48 h for measurement of transporter activity. To date, substrates and/or inhibitors that are specific for each MRP family member have not been defined; thus, it is difficult to distinguish the activity of MRP3 from that of other MRP transporters that are also expressed in the cell lines studied. We used the 5-carboxyfluorescein (5-CF) assay as previously described (Lee and Piquette-Miller, 2001) to measure total MRP activity. In this assay, the cells were preincubated with 2 µM 5-carboxyflourescein diacetate, which is nonfluorescent but is metabolized by intracellular esterases to the fluorescent anion 5-CF. 5-CF has been shown to be a specific substrate of the MRP family of transporters but does not differentiate between individual MRPs (Van der Kolk et al., 1998). The relative cellular retention of 5-CF was then measured in the absence and presence of the MRP-specific inhibitor indomethacin at a concentration that has been shown to maximally inhibit MRP-mediated efflux (Draper et al., 1997, Lee and Piquette-Miller, 2001), and MRP-mediated transport activity was thus estimated specifically as the difference in cellular retention of 5-CF in the presence of indomethacin versus its absence.

For the in vivo studies, 8-week-old male C57/BL-6 mice (25-30 g) from Charles River Canada (St. Constant, QC, Canada) and PXR-null (PXR^-/-) mice (kindly provided by Dr. Christopher Sinal, Dalhousie University, Halifax, NS, Canada with permission from Dr. Steven Kliewer, University of Texas Southwestern Medical Center, Dallas, TX) were maintained in a temperature-controlled facility with 12-h light/dark cycles and were fed a standard chow diet. The treated mice (n = 4) were injected i.m. on the same hind leg each day with 50 mg/kg (dissolved in corn oil) of the PXR activator RU486 for 3 days, whereas the control mice (n = 4) received an i.m. injection of the corn oil vehicle control. At the end of the treatment period, all mice were sacrificed by cervical dislocation, and the livers were removed and frozen at -80°C until analysis. Levels of MRP3, MRP2, PXR, and CYP3A11 mRNA were determined by RT-PCR after isolation of total RNA and were normalized to 18S rRNA band optical densities. PCR primer sequences have been previously reported (Hartmann et al., 2002; Yamada et al., 2002).

All studies were performed in duplicate using n = 3 or more. The Student's t test was used to calculate significance, with p < 0.05 considered to be statistically significant. Analysis was performed using SigmaStat 2.03 (SPSS Inc., Chicago, IL).

	Results and Discussion

Top Abstract Materials and Methods Results and Discussion References

 
Effect of PXR Activators on MRP3 Expression in Vitro. PXR mRNA was expressed at detectable levels in both HuH7 and HepG2 cells. Interestingly, both cell lines also expressed the previously described splice variant of PXR (Dotzlaw et al., 1999). Similar to previous studies (Lee and Piquette-Miller, 2001), HepG2 cells were found to express detectable levels of MDR1, MRP1, MRP2, MRP3, and MRP6 transporters, whereas HuH7 cells expressed only MDR1, MRP3, and MRP6 (data not shown).

Treatment of HuH7 cells with various PXR activators resulted in an up-regulation of MRP3 mRNA levels in a time- and dose-dependent manner (Fig. 1, a and b). Clotrimazole was the most potent inducer, as MRP3 expression increased 5- to 6-fold at concentrations of 10 to 25 µM. Rifampicin and RU486 caused greater than 4-fold induction using 25 µM, and metyrapone, nifedipine, PCN, and the bile acid lithocholic acid (LCA) also caused significant induction (Fig. 1a). Concentrations of activators used did not significantly affect cell viability (>90%) as determined by the MTT assay except 100 µM LCA, which caused a 20% loss of viability. This may explain why MRP3 expression at this concentration was less than that seen with 50 µM. Maximal induction of MRP3 was seen at 24 h of treatment. A representative time course for rifampicin (10 µM) induction is shown in Fig. 1b. Levels of MRP6 mRNA, on the other hand, were not significantly altered after treatment of cells with rifampicin (Fig. 1b) or any of the other PXR activators. Maglich et al. (2002) showed that expression of PXR is autoregulated in that activation of PXR in human liver regulates the expression of PXR itself. To confirm PXR activation we examined PXR mRNA levels in these studies. As anticipated, we found that the expression of PXR mRNA was significantly induced after 24 h of treatment with PXR activators (Fig. 1c).

View larger version (37K): [in this window] [in a new window]   FIG. 1. Effect of PXR activators on mRNA expression in HuH7 cells. a, MRP expression. Cells were incubated (n = 4) with 0.1% dimethyl sulfoxide vehicle control () or two concentrations (, ) of PXR activators for 24 h, followed by RNA isolation and RT-PCR to quantify mRNA as described under Materials and Methods. Clotrimazole (Clot.), rifampicin (Rif.), RU486, nifedipine (Nifed.), and PCN were used at 10- and 25-µM concentrations, whereas 50 and 100 µM of LCA and 0.5 and 1 mM concentrations of metyrapone (Metyr.) were used. b, RT-PCR image. Cells were incubated (n = 3) with vehicle control or 10 µM rifampicin for 6, 24, or 48 h, followed by RNA isolation and RT-PCR to quantify MRP3, MRP6, and GAPDH mRNA as described under Materials and Methods. c, PXR expression. Cells were incubated with 25 µM clotrimazole, rifampicin, RU486, nifedipine, PCN, 1 mM metyrapone, or 50 µM LCA for 24 h followed by RT-PCR analysis of PXR mRNA levels. Bars represent the percentage mean values ± S.E.M. of the band optical density normalized to GAPDH compared with controls (*, p < 0.05).

MRP functional activity in HuH7 cells was measured by the cellular retention of the fluorescent MRP substrate 5-CF in the presence of the MRP inhibitor indomethacin. Increased activity was consistent with MRP3 mRNA induction and reached a maximum at 48 h (Fig. 2). Although 5-CF is a nonspecific MRP substrate as discussed earlier, the increased activity observed in the HuH7 cells is likely reflective of MRP3 induction, as HuH7 cells only express MRP3 and MRP6 and mRNA levels of MRP6 were not affected by treatment with the PXR activators (Fig. 1b).

View larger version (21K): [in this window] [in a new window]   FIG. 2. Effect of PXR activators on MRP transport activity in HuH7 cells. Cells were incubated (n = 3) with vehicle control () or a PXR activator for 24 () or 48 h (), followed by measurement of 5-CF cellular retention as described under Materials and Methods. Treatments included 10 µM rifampicin (Rifamp.), 20 µM RU486, 500 µM metyrapone (Metyr.), and 20 µM nifedipine (Nifed.). Bars represent the percentage of mean values ± S.E.M. of transport activity compared with controls (*, p < 0.05).

The effect of PXR activators on MRP3 mRNA expression in HepG2 cells was also studied to confirm MRP3 induction with PXR activation. Treatment of HepG2 cells with 25 µM clotrimazole or rifampicin for 24 h also induced MRP3 expression in HepG2 cells, with mRNA levels increasing 3.2- and 1.9-fold, respectively (p < 0.05). However, induction of MRP3 in HepG2 cells was less than half that in HuH7 cells. This likely occurs due to the fact that HepG2 cells express additional MRP transporters including MRP1 and MRP2. The presence of these transporters in HepG2 cells may diminish the importance of extensive MRP3 up-regulation in response to xenobiotics. Indeed, MRP2 mRNA expression was also induced by approximately 2-fold in clotrimazole and rifampicin-treated HepG2 cells (p < 0.05).

Effect of PXR Activation on MRP3 Expression in Vivo. The impact of PXR activation on hepatic MRP3 expression in vivo was examined in wild-type and PXR-null mice using the PXR activator RU486. In wild-type mice, a 3-day treatment of RU486 (50 mg/kg, i.m.) resulted in a significant 1.5-fold induction of MRP3 mRNA (Fig. 3). MRP2 and CYP3A11 mRNA levels were also significantly induced 1.5- and 1.4-fold, respectively, in these mice. Induction of MRP2 and CYP3A11 by PXR activation with RU486 or other xenobiotics is consistent with previous in vivo and in vitro studies in humans and rodents (Bertilsson et al., 1998; Beigneux et al., 2002; Kast et al., 2002). RU486 treatment also induced PXR mRNA levels in wild-type mice significantly by 1.3-fold, which is consistent with our in vitro studies. To verify that the up-regulation by RU486 was due to an effect on PXR, we examined the effect of RU486 treatment on MRP3 mRNA expression in PXR^-/- mice (Fig. 3). In contrast to the wild-type mice, we found that there was no increase in the mRNA expression of MRP3 in PXR^-/- mice. Furthermore, the mRNA levels of MRP2 and CYP3A11 were also not affected by RU486 in PXR^-/- mice. This confirms that PXR is involved in the up-regulation of MRP3 mRNA expression.

View larger version (37K): [in this window] [in a new window]   FIG. 3. Effect of RU486 on hepatic MRP3, MRP2, CYP3A11, and PXR mRNA expression in vivo in wild-type and PXR-/- mice. Mice were treated with corn oil vehicle control () or 50 mg/kg RU486 i.m. daily for 3 days (, wild-type; , PXR-/-). Then the livers were collected for mRNA quantification by RT-PCR and normalized to 18 S rRNA as described under Materials and Methods. Bars represent the percentage of mean values ± S.E.M. of efflux compared with controls (*, p < 0.05).

The treatment of both human hepatoma cell lines and mice with various PXR activators resulted in the induction of MRP3 mRNA and functional activity. Although mRNA stability of the MRP3 gene could be affected, PXR is known to primarily cause induction through activation of transcriptional activity. We used a range of PXR activators, and the extent of MRP3 mRNA induction corresponded well with the potency of human PXR activation as found by others (Moore et al., 2000). Results with clotrimazole were surprising in that it was a more effective up-regulator of MRP3 than rifampicin, despite rifampicin having a lower EC₅₀ value for PXR activation. However, this may be due to additional effects of clotrimazole, such as the activation of other nuclear receptors or transcription factors that also regulate MRP3. PCN, which is used primarily as a rodent PXR activator, can also activate human PXR with low potency (Moore et al., 2000), and this is reflected by only a slight induction of MRP3 in human cell lines. Most importantly, MRP3 induction did not occur in RU486-treated PXR^-/- mice, indicating that the induction seen in wild-type mice occurred via PXR. Therefore, the likelihood is great that the increase in MRP3 mRNA that we observed is due to PXR activation and a subsequent increase in MRP3 transcription; however, further studies are required. Overall, our results suggest that activation of PXR may play a role in the regulation of MRP3 expression and may thus serve as an additional protective mechanism against xenobiotic and bile acid toxicity.

Shirley Teng
Veronika Jekerle
Micheline Piquette-Miller

Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

	Acknowledgments

 
We thank Georgy Hartmann for skillful technical assistance.

	Footnotes

 
¹ Abbreviations used are: PXR, pregnane X receptor; MRP, multidrug resistance-associated protein; PCN, 5-pregnen-3ß-ol-20-one-16-carbonitrile; RU486, 17ß-hydroxy-11ß-[4-dimethylamino phenyl]-17-[1-propynyl]estra-4,9-dien-3-one; RT-PCR, reverse transcription-polymerase chain reaction; GAPDH, glyceraldehye-3-phosphate dehydrogenase; 5-CF, 5-carboxyfluorescein; LCA, lithocholic acid; MTT, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide.

Address correspondence to: Prof. Micheline Piquette-Miller, Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario, Canada, M5S 2S2. E-mail: m.piquette.miller{at}utoronto.ca

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This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Teng, S. Articles by Piquette-Miller, M. Search for Related Content PubMed PubMed Citation Articles by Teng, S. Articles by Piquette-Miller, M.