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Division of Experimental Therapy [A. E. v. H., J. W. J., E. W., R. F. B., A. H. S.] and Divisions of Experimental Therapy and Medical Oncology [J. H. M. S.], The Netherlands Cancer Institute, 1066 CX Amsterdam, and Department of Pharmacy and Pharmacology, Slotervaart Hospital, 1066 EC Amsterdam [J. H. B.], The Netherlands
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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BCRP is a member of the ABC family of drug transporters. It can actively transport various anticancer drugs (doxorubicin, mitoxantrone, and topotecan) from cells, causing multidrug resistance (15 , 16) . The mouse homologue Bcrp1 is present in the apical membrane of epithelial cells of the small intestine, colon, cecum, and renal proximal tubules, in hepatic bile canalicular membranes, and in placental labyrinth cells (17 , 18) . We previously demonstrated that this enables Bcrp1 to decrease the oral uptake and fetal penetration of topotecan and dietary compounds (17 , 18) . Because BCRP/Bcrp1 plays a role in the (re-)uptake from the gut, the hepatobiliary excretion and the overall clearance of topotecan and presumably other BCRP substrates, we were interested in the possible role of Bcrp1 in the bioavailability of dietary carcinogens such as PhIP.
If BCRP would have a role in protection from food carcinogens, then inter- or intraindividual variation in BCRP activity, as a consequence of induction, stimulation, or inhibition of BCRP by food or drug intake or because of BCRP polymorphisms, could be important to individual cancer susceptibility (19 , 20) . Dietrich et al. (21 , 22) established that the ABC transporter MRP2 transports PhIP and affects its oral uptake and excretion using Mrp2 mutant rats. There might be analogous roles for BCRP and the ABC transporter P-gp because all three transporters are present in the apical membranes of small intestine and bile canalicular membrane. Each could thus potentially influence the bioavailability of xenotoxins and carcinogens. In this study, we addressed the question whether Bcrp1 and P-gp can transport PhIP and can affect its bioavailability by in vitro and in vivo studies using Bcrp1- and P-gp-knockout mice.
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MATERIALS AND METHODS |
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Chemicals.
PhIP and [14C]PhIP (10 mCi/mmol) were from Toronto Research Chemicals, Inc. (Toronto, Ontario, Canada); [3H]]Inulin was from Amersham Pharmacia Biotech (Little Chalfont, Buckinghamshire, United Kingdom); ketamine (Ketanest-S) was from Parke-Davis (Hoofddorp, the Netherlands); xylazine was from Sigma Chemical Co. (St. Louis, MO); methoxyflurane (Metofane) was from Medical Developments Australia Pty. Ltd. (Springvale, Victoria, Australia); GF120918 was from GlaxoSmithKline (Research Triangle Park, North Carolina, USA); Ko143 was described previously (23)
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Cells and Tissue Culture.
The polarized pig kidney epithelial cell line LLC-PK1 and the polarized canine kidney cell line MDCK-II were used in the transport assays. Human MDR1-, and murine Mdr1a-, Mdr1b-, and Bcrp1-transfected LLC-PK1 subclones were described previously (17
, 24
, 25)
. The LLC-PK1 cells and transfected subclones were cultured in M199 medium supplied with L-glutamine (Life Technologies, Inc., Breda, the Netherlands) and supplemented with penicillin (50 units/ml), streptomycin (50 µg/ml) and 10% (v/v) FCS (Life Technologies, Inc.) at 37°C in the presence of 5% CO2. Human MDR1-, murine Bcrp1-, and human MRP2-transduced MDCK-II subclones were described previously (17
, 26)
. The MDCK-II cells and transduced subclones were cultured in DMEM supplied with glutamax (Life Technologies, Inc.) and supplemented with penicillin (50 units/ml), streptomycin (50 µg/ml), and 10% (v/v) FCS (Life Technologies, Inc.) at 37°C in the presence of 5% CO2.
Transport Assay.
Transport assays were carried out as described with minor modifications (24)
. Cells were seeded on microporous polycarbonate membrane filters (3.0-µm pore size, 24 mm diameter, Transwell 3414; Costar, Corning, NY) at a density of 2.0 x 106 cells/well in 2 ml of complete medium. Cells were grown for 3 days, and medium was replaced every day. Two h before the start of the experiment, medium at both the apical and basolateral side of the monolayer was replaced with 2 ml of Optimem medium (Life Technologies, Inc.) without serum, either with or without 5 µM GF120918 or Ko143. The experiment was started (t = 0) by replacing the medium in either the apical or basolateral compartment with fresh Optimem medium, either with or without 5 µM GF120918 or Ko143 and 2 or 100 µM [14C]PhIP and [3H]]inulin. Cells were incubated at 37°C in 5% CO2, and 50 µl of aliquots were taken every hour. The appearance of radioactivity in the opposite compartment was measured and presented as the fraction of total radioactivity added at the beginning of the experiment. The tightness of the monolayer was measured by monitoring the paracellular flux of [3H]]inulin to the opposite compartment, which had to remain <1.5% of the total radioactivity/hour.
Pharmacokinetic Experiments.
For i.v. administration of [14C]PhIP, 5 µl of drug solution [appropriate concentration in 20% (v/v) DMSO, 4% (w/v) D-glucose]/g body weight was injected into the tail vein of mice lightly anesthetized with methoxyflurane. For oral administration, 5.3 µl of drug solution [appropriate concentration in 5.8% (v/v) DMSO, 4.7% (w/v) D-glucose, 0.01 M HCl]/g body weight were dosed by gavage into the stomach. Animals were sacrificed by terminal bleeding through cardiac puncture after anesthesia with methoxyflurane. Levels of radioactivity in plasma and urine were determined by liquid scintillation counting.
Metabolic Cage Experiment.
Mice were housed in a Ruco Type M/1 metabolic cage (Valkenswaard, the Netherlands). They were allowed to accustom to the cages for 2 days, before receiving [14C]PhIP (1 mg/kg) injected into the tail vein under light anesthesia with methoxyflurane. Feces and urine were collected in fractions of 0–4, 4–8, 8–24, and 24–48 h after drug administration, and feces was homogenized in 4% (w/v) BSA. Levels of radioactivity in feces and urine were determined by liquid scintillation counting.
Gall Bladder Cannulation Experiments.
Mice were anesthetized with a combination of ketamine (25 mg/ml) and xylazine to a final dose of 116 mg/kg ketamine and 8 mg/kg xylazine. The volume of the anesthetic solution injected i.p. was 5 µl/g body weight. After opening of the abdominal cavity and distal ligation of the common bile duct, a polythene catheter (Portex Limited, Hythe, United Kingdom), with an inner diameter of 0.28 mm, was inserted into the incised gall bladder. The catheter was fixed to the gall bladder with an additional ligation. Bile was collected in 10-min fractions for 60 min after i.v. injection of [14C]PhIP (1 mg/kg) into the tail vein. At the end of the experiment, blood was collected by cardiac puncture, and organs were removed and homogenized in 4% (w/v) BSA. Intestinal contents (feces) were separated from intestinal tissue. Levels of radioactivity in plasma, bile, feces, and tissue homogenates were determined by liquid scintillation counting.
Pharmacokinetic Calculations and Statistical Analysis.
All values are given as average ± SD, unless indicated otherwise. A two-sample equal variance (homoscedastic) Student’s t test was used to assess the significance of difference between two sets of data. Differences were considered to be statistically significant when P < 0.05. AUC from time = 0 to the last sampling point was calculated by the linear trapezoidal rule, and oral availability was determined by AUC p.o./AUC i.v. at a dose of 1 mg/kg.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. In the MDR1-transduced MDCK-II cells, there was somewhat increased apical and decreased basolateral translocation, whereas in the Bcrp1-transduced MDCK-II cell line, apically directed translocation was highly increased and basolaterally directed translocation drastically decreased (Fig. 1, C and D)
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. In the Bcrp1-transfected LLC-PK1 subclone, apically directed translocation was highly increased and basolaterally directed translocation was highly decreased compared with the parental LLC-PK1 parent cell line (Fig. 2C)
. This transport was completely inhibited by Ko143, a selective Bcrp1 inhibitor (Fig. 2D
; Ref. 23
) and partially by the Bcrp1/P-gp inhibitor GF120918 (Fig. 2E
; Ref. 27
). This suggests that Ko143 is a better inhibitor of Bcrp1 than GF120918, consistent with Allen et al. (23)
, and that PhIP transport by Bcrp1 is not easily completely inhibited. The high background transport of [14C]PhIP in parental LLC-PK1 cells (especially observed at 2 µM [14C]PhIP) was most likely attributable to endogenous pig BCRP because this endogenous transport was nearly completely inhibited by both GF120918 and Ko143 (data not shown).
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In Vivo Plasma Pharmacokinetics of [14C]PhIP in Bcrp1-/-, Mdr1a/b-/-, and Wild-Type Mice.
To assess whether the in vitro observed Bcrp1- and Mdr1a- mediated PhIP transport is also relevant in vivo, we tested the oral uptake of [14C]PhIP in wild-type, Mdr1a/b-/-, and Bcrp1-/- mice. One h after oral [14C]PhIP administration at 1 mg/kg, [14C]PhIP plasma levels of the Bcrp1-/- mice were increased 3.1-fold compared with the wild-type mice (144 ± 22 versus 46.3 ± 4.3 ng/ml, P < 0.002). In contrast, [14C]PhIP plasma levels in the Mdr1a/b-/- mice did not differ from those in the wild-type mice (46.0 ± 18 versus 46.3 ± 4.3 ng/ml, P = 0.98).
The clear impact of the Bcrp1 genotype on oral [14C]PhIP uptake incited a more extensive analysis of the underlying processes. We administered [14C]PhIP (1 mg/kg) either p.o. or i.v. to Bcrp1-/- and wild-type mice. We observed that 15 min after oral administration, the plasma [14C]PhIP level had already reached its maximum, suggesting rapid absorption from the intestines and rapid distribution and clearance (Fig. 3A)
. Plasma [14C]PhIP levels also decreased quickly after i.v. administration (Fig. 3B)
, indicating a high distribution rate of PhIP and possibly a high clearance rate by liver and/or kidneys (see below). Within 7.5 min after i.v. administration, [14C]PhIP plasma levels were lower in wild-type than in Bcrp1-/- mice, indicating that clearance/distribution differences arose early (Fig. 3B)
. Semilog plotting of the data showed that between 15 and 120 min after i.v. administration, the elimination rate constant was comparable between Bcrp1-/- and wild-type mice (data not shown).
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Fecal and Urinary Excretion of [14C]PhIP in Bcrp1-/- and Wild-Type Mice.
To determine the extent to which fecal and urinary excretion contribute to PhIP clearance in nonanesthetized mice, [14C]PhIP (1 mg/kg) was administered i.v. to Bcrp1-/-, and wild-type mice housed in metabolic cages and fecal and urinary radioactivity was measured. Most of the radioactivity in urine was excreted during the first 0–4 h. Radioactivity in feces was at its highest between 4 and 8 h and lower in the later time fractions (data not shown). In wild-type mice, 70.4 ± 8.1% of the administered radioactivity was recovered from the feces over the 48 h after administration of [14C]PhIP, indicating that fecal excretion is the main excretory pathway for [14C]PhIP (Fig. 4)
. Fecal excretion diminished 2.7-fold in Bcrp1-/- mice (26.6 ± 5.0%, P < 0.0001). This suggests a prominent role for Bcrp1 in the fecal excretion of [14C]PhIP. Radioactivity excretion had shifted to the urinary route, which was 2.4-fold increased in Bcrp1-/- compared with wild-type mice (79.3 ± 15.3 versus 33.0 ± 2.5%, P < 0.0001; Fig. 4
).
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. There was a relatively high accumulation of radioactivity in the kidney. Radioactivity levels in testis, spleen, and brain were comparatively low (Table 1)
. The [14C]PhIP levels were considerably higher in small intestinal tissue of wild-type versus Bcrp1-/- mice, especially when corrected for the lower plasma levels. This higher tissue level probably reflects the much higher accumulation and concentration of [14C]PhIP in the contents of the small intestine of wild-type mice (Table 1)
: the percentage of the dose [14C]PhIP retrieved from the content of small intestines after 1 h was 2.8-fold higher in wild-type compared with Bcrp1-/- mice (4.2 ± 1.5 versus 1.5 ± 0.8%, P < 0.004; Fig. 5
), indicating Bcrp1-mediated transport of [14C]PhIP directly into the lumen of this organ. In the same experiment, we also measured the biliary excretion of [14C]PhIP in fractions of 10 min. All bile fractions from Bcrp1-/- animals demonstrated a significantly decreased excretion of [14C]PhIP into bile compared with wild-type mice (P < 0.0004; Fig. 6
). At 1 h after i.v. administration, the cumulative [14C]PhIP excretion, as percentage of the dose, was 9.0 ± 4.4% versus 36.5 ± 9.4% in Bcrp1-/- and wild-type mice, respectively. This indicates that 75% of the [14C]PhIP biliary excretion over 1 h can be attributed to Bcrp1 function [1- (0.090/0.365)]. We conclude from these experiments that the hepatobiliary elimination of [14C]PhIP (at this dosage) in mice is extensive and dominated by Bcrp1 activity.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Extrapolating these results to humans, it is possible that BCRP will affect the susceptibility of humans to PhIP-induced carcinogenesis because human BCRP and mouse Bcrp1 appear to be very similar with respect to transported substrates (23) . Inhibition of BCRP by drug intake, as well as the existence of BCRP polymorphisms, can cause inter- and intraindividual variation in BCRP activity (19 , 20) . Possibly, induction and stimulation of BCRP by food and drug intake is also involved. This may affect the exposure to food carcinogens such as PhIP, with possible consequences for individual differences in cancer susceptibility. Some dose optimization strategies for drugs with narrow therapeutic windows involve the coadministration of transporter inhibitors. When such inhibitors [for instance GF120918 (28) ] are applied chronically to increase the oral availability of P-gp and BCRP substrate drugs, they may thereby also increase the bioavailability of PhIP and possibly other food carcinogens. Given these considerations, it will be of interest to address the possible consequences of variation in BCRP/Bcrp1 activity for dietary carcinogen susceptibility, using the Bcrp1-/- mouse model as a tool.
We found a comparatively minor role in [14C]PhIP transport for Mdr1a P-gp in vitro, and no indication for significant effects of Mdr1a P-gp in vivo. In addition, we did not detect significant transport of [14C]PhIP by human MRP2 in vitro. This appears to contrast with the study of Dietrich et al. (21) , who did observe in vitro transport of PhIP in the same cell line, albeit at very low concentration (50 nM). Despite the low PhIP transport by human MRP2, in vivo studies of PhIP in wild-type and Mrp2-deficient rats revealed pharmacokinetic effects that appear to be quantitatively comparable with what we observed in Bcrp1-/- mice with respect to PhIP oral availability and hepatobiliary excretion. In fact, Dietrich et al. (22) could attribute a 77% decrease in hepatobiliary excretion of PhIP to loss of Mrp2 activity. Although the PhIP dosage used in the rat studies was probably lower than in our mouse study, it is striking that we found a 75% decrease in hepatobiliary excretion of PhIP because of absence of murine Bcrp1. Taken together, these studies suggest that both Mrp2 and Bcrp1 can play a major role in the hepatobiliary disposition and oral availability of PhIP, although there may also be species differences between rats, mice, and humans in this respect. In any case, in future studies it will be interesting to assess the relative impact of BCRP/Bcrp1 and MRP2/Mrp2 on dietary carcinogens.
Whereas AUCs p.o. between Bcrp1-/- and wild-type mice differ 2.9-fold, the oral availability of PhIP (AUC p.o./AUC i.v.) is only modestly increased in Bcrp1-/- mice (from 60% in wild-type to 79% in Bcrp1-/- mice) because of a 2.2 fold higher AUC i.v. As is also evident from the hepatobiliary and direct intestinal elimination data, this indicates a more pronounced role for Bcrp1 in hepatobiliary elimination of PhIP compared with directly reducing uptake of PhIP from the intestine.
The absence of Bcrp1 resulted in a major shift of PhIP elimination from predominantly fecal to predominantly renal elimination. At first sight, this might seem somewhat surprising because a high level of Bcrp1 is found in the renal proximal tubules (18) , and its absence in the Bcrp1-/- mice would be expected to result in a decreased renal elimination of PhIP. Apparently, however, when the hepatobiliary and direct intestinal elimination of PhIP is nearly abrogated in Bcrp1-/- mice, the kidney can still readily eliminate the excess of PhIP. This might occur primarily by glomerular filtration or perhaps also by other remaining active renal transporters for PhIP (such as Mrp2). The higher plasma PhIP levels in the Bcrp1-/- mice will no doubt also enhance this renal elimination.
The tissue distribution of [14C]PhIP was particularly interesting for brain because some studies show that BCRP is present in the human blood-brain barrier in analogy with P-gp (29) , and preliminary immunohistochemistry data also suggest Bcrp1 presence in mouse brain capillaries (data not shown). For this single time point, however, at least for PhIP as a substrate, we did not observe a significantly increased brain penetration in Bcrp1-/- mice when corrected for the increased plasma level. Allowing for the limitations of a single time point experiment, the results suggest that Bcrp1 does not play a major role in restricting brain penetration of PhIP.
Finally, we note that this study adds yet another functional class to the growing number of transported BCRP/Bcrp1 substrates. Next to a range of anticancer drugs, dyes such as Hoechst 33342 used for selecting stem cells (30) , and pheophorbide a, a natural phototoxin derived from chlorophyll (18) , a relatively small HA carcinogen also appears to be part of the substrate spectrum. In view of the considerable diversity in size, structure, and charge (ranging from weak bases to negatively charged compounds such as methotrexate) and biological functions of known BCRP/Bcrp1 substrates, one can reasonably expect that many more medically and toxicologically relevant compounds will also be affected by this transporter.
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FOOTNOTES |
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1 This project was, in part, financially supported by the Dutch Cancer Society Grant NKI 2000-2271. 
2 To whom requests for reprints should be addressed, at Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. E-mail: a.schinkel{at}nki.nl
3 The abbreviations used are: HA, heterocyclic amine; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; ABC, ATP-binding cassette; BCRP, breast cancer resistance protein; P-gp, P-glycoprotein; AUC, area under the plasma concentration-time curve.
Received 4/10/03. Revised 6/25/03. Accepted 7/ 9/03.
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M. L. H. Vlaming, K. Mohrmann, E. Wagenaar, D. R. de Waart, R. P. J. O. Elferink, J. S. Lagas, O. van Tellingen, L. D. Vainchtein, H. Rosing, J. H. Beijnen, et al. Carcinogen and Anticancer Drug Transport by Mrp2 in Vivo: Studies Using Mrp2 (Abcc2) Knockout Mice J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 319 - 327. [Abstract] [Full Text] [PDF]
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H. Saito, H. Hirano, H. Nakagawa, T. Fukami, K. Oosumi, K. Murakami, H. Kimura, T. Kouchi, M. Konomi, E. Tao, et al. A New Strategy of High-Speed Screening and Quantitative Structure-Activity Relationship Analysis to Evaluate Human ATP-Binding Cassette Transporter ABCG2-Drug Interactions J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1114 - 1124. [Abstract] [Full Text] [PDF]
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 H. Wang, L. Zhou, A. Gupta, R. R. Vethanayagam, Y. Zhang, J. D. Unadkat, and Q. Mao Regulation of BCRP/ABCG2 expression by progesterone and 17beta-estradiol in human placental BeWo cells Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E798 - E807. [Abstract] [Full Text] [PDF]
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K.-i. Nezasa, X. Tian, M. J. Zamek-Gliszczynski, N. J. Patel, T. J. Raub, and K. L. R. Brouwer ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2',7'-DICHLOROFLUORESCEIN IN Abcg2 (Bcrp1) AND Abcc2 (Mrp2) KNOCKOUT MICE Drug Metab. Dispos., April 1, 2006; 34(4): 718 - 723. [Abstract] [Full Text] [PDF]
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G. Merino, A. I. Alvarez, M. M. Pulido, A. J. Molina, A. H. Schinkel, and J. G. Prieto BREAST CANCER RESISTANCE PROTEIN (BCRP/ABCG2) TRANSPORTS FLUOROQUINOLONE ANTIBIOTICS AND AFFECTS THEIR ORAL AVAILABILITY, PHARMACOKINETICS, AND MILK SECRETION Drug Metab. Dispos., April 1, 2006; 34(4): 690 - 695. [Abstract] [Full Text] [PDF]
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A. E.v. Herwaarden, E. Wagenaar, B. Karnekamp, G. Merino, J. W. Jonker, and A. H. Schinkel Breast cancer resistance protein (Bcrp1/Abcg2) reduces systemic exposure of the dietary carcinogens aflatoxin B1, IQ and Trp-P-1 but also mediates their secretion into breast milk Carcinogenesis, January 1, 2006; 27(1): 123 - 130. [Abstract] [Full Text] [PDF]
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B. Ebert, A. Seidel, and A. Lampen Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists Carcinogenesis, October 1, 2005; 26(10): 1754 - 1763. [Abstract] [Full Text] [PDF]
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M. Hirano, K. Maeda, S. Matsushima, Y. Nozaki, H. Kusuhara, and Y. Sugiyama Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin Mol. Pharmacol., September 1, 2005; 68(3): 800 - 807. [Abstract] [Full Text] [PDF]
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H. Tahara, H. Kusuhara, E. Fuse, and Y. Sugiyama P-GLYCOPROTEIN PLAYS A MAJOR ROLE IN THE EFFLUX OF FEXOFENADINE IN THE SMALL INTESTINE AND BLOOD-BRAIN BARRIER, BUT ONLY A LIMITED ROLE IN ITS BILIARY EXCRETION Drug Metab. Dispos., July 1, 2005; 33(7): 963 - 968. [Abstract] [Full Text] [PDF]
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T. Takada, H. Suzuki, Y. Gotoh, and Y. Sugiyama REGULATION OF THE CELL SURFACE EXPRESSION OF HUMAN BCRP/ABCG2 BY THE PHOSPHORYLATION STATE OF AKT IN POLARIZED CELLS Drug Metab. Dispos., July 1, 2005; 33(7): 905 - 909. [Abstract] [Full Text] [PDF]
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R. R. Vethanayagam, H. Wang, A. Gupta, Y. Zhang, F. Lewis, J. D. Unadkat, and Q. Mao FUNCTIONAL ANALYSIS OF THE HUMAN VARIANTS OF BREAST CANCER RESISTANCE PROTEIN: I206L, N590Y, AND D620N Drug Metab. Dispos., June 1, 2005; 33(6): 697 - 705. [Abstract] [Full Text] [PDF]
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A. L. A. Sesink, I. C. W. Arts, V. C. J. de Boer, P. Breedveld, J. H. M. Schellens, P. C. H. Hollman, and F. G. M. Russel Breast Cancer Resistance Protein (Bcrp1/Abcg2) Limits Net Intestinal Uptake of Quercetin in Rats by Facilitating Apical Efflux of Glucuronides Mol. Pharmacol., June 1, 2005; 67(6): 1999 - 2006. [Abstract] [Full Text] [PDF]
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G. Merino, J. W. Jonker, E. Wagenaar, M. M. Pulido, A. J. Molina, A. I. Alvarez, and A. H. Schinkel TRANSPORT OF ANTHELMINTIC BENZIMIDAZOLE DRUGS BY BREAST CANCER RESISTANCE PROTEIN (BCRP/ABCG2) Drug Metab. Dispos., May 1, 2005; 33(5): 614 - 618. [Abstract] [Full Text] [PDF]
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G. Merino, J. W. Jonker, E. Wagenaar, A. E. van Herwaarden, and A. H. Schinkel The Breast Cancer Resistance Protein (BCRP/ABCG2) Affects Pharmacokinetics, Hepatobiliary Excretion, and Milk Secretion of the Antibiotic Nitrofurantoin Mol. Pharmacol., May 1, 2005; 67(5): 1758 - 1764. [Abstract] [Full Text] [PDF]
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G. Merino, A. E. van Herwaarden, E. Wagenaar, J. W. Jonker, and A. H. Schinkel Sex-Dependent Expression and Activity of the ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (BCRP/ABCG2) in Liver Mol. Pharmacol., May 1, 2005; 67(5): 1765 - 1771. [Abstract] [Full Text] [PDF]
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 A. H. Schinkel Functions of the ABC transporter breast cancer resistance protein (BCRP/ABCG2) AACR Meeting Abstracts, April 1, 2005; 2005(1): 1475 - 1476. [Abstract]
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Y. Adachi, H. Suzuki, A. H. Schinkel, and Y. Sugiyama Role of Breast Cancer Resistance Protein (Bcrp1/Abcg2) in the Extrusion of Glucuronide and Sulfate Conjugates from Enterocytes to Intestinal Lumen Mol. Pharmacol., March 1, 2005; 67(3): 923 - 928. [Abstract] [Full Text] [PDF]
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 Y. Imai, E. Ishikawa, S. Asada, and Y. Sugimoto Estrogen-Mediated Post transcriptional Down-regulation of Breast Cancer Resistance Protein/ABCG2 Cancer Res., January 15, 2005; 65(2): 596 - 604. [Abstract] [Full Text] [PDF]
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 T. Ueda, S. Brenner, H. L. Malech, S. M. Langemeijer, S. Perl, M. Kirby, O. A. Phang, A. E. Krouse, R. E. Donahue, E. M. Kang, et al. Cloning and Functional Analysis of the Rhesus Macaque ABCG2 Gene: FORCED EXPRESSION CONFERS AN SP PHENOTYPE AMONG HEMATOPOIETIC STEM CELL PROGENY IN VIVO J. Biol. Chem., January 14, 2005; 280(2): 991 - 998. [Abstract] [Full Text] [PDF]
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Y.-J. Lee, H. Kusuhara, J. W. Jonker, A. H. Schinkel, and Y. Sugiyama Investigation of Efflux Transport of Dehydroepiandrosterone Sulfate and Mitoxantrone at the Mouse Blood-Brain Barrier: A Minor Role of Breast Cancer Resistance Protein J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 44 - 52. [Abstract] [Full Text] [PDF]
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P. Pavek, G. Merino, E. Wagenaar, E. Bolscher, M. Novotna, J. W. Jonker, and A. H. Schinkel Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 144 - 152. [Abstract] [Full Text] [PDF]
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 C G Dietrich, A Geier, H E Wasmuth, S Matern, C Gartung, D R de Waart, and R P J O Elferink Influence of biliary cirrhosis on the detoxification and elimination of a food derived carcinogen Gut, December 1, 2004; 53(12): 1850 - 1855. [Abstract] [Full Text] [PDF]
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N. Mizuno, M. Suzuki, H. Kusuhara, H. Suzuki, K. Takeuchi, T. Niwa, J. W. Jonker, and Y. Sugiyama IMPAIRED RENAL EXCRETION OF 6-HYDROXY-5,7-DIMETHYL-2-METHYLAMINO-4-(3-PYRIDYLMETHYL) BENZOTHIAZOLE (E3040) SULFATE IN BREAST CANCER RESISTANCE PROTEIN (BCRP1/ABCG2) KNOCKOUT MICE Drug Metab. Dispos., September 1, 2004; 32(9): 898 - 901. [Abstract] [Full Text] [PDF]
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); translocation from the apical to the basolateral compartment (
). Error bars (often smaller than the symbols) indicate SD.
