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Uva-DARE (Digital Academic Repository) UvA-DARE (Digital Academic Repository) Pharmacological and physiological functions of polyspecific drug transporters Jonker, J.W. Publication date 2003 Link to publication Citation for published version (APA): Jonker, J. W. (2003). Pharmacological and physiological functions of polyspecific drug transporters. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:01 Oct 2021 Chapterr 4 Thee breast cancer resistance protein protects against a major chlorophyll-derivedd dietary phototoxin andd protoporphyria Johann W. Jonker, Marije Buitelaar, Els Wagenaar, Martin A. van der Valk, Georgee L. Scheffer, Rik J. Scheper, Torsten Plösch, Folkert Kuipers, Ronaldd P.J. Oude Elferink, Hilde Rosing, Jos H. Beijnen and Alfred H. Schinkel Proc.Proc. Natl. Acad. Set. USA (2002) 99: 15649-J5654 BCRPBCRP protects against a dietary phototo.xin Thee breast cancer resistance protein protects against aa major chlorophyll-derived dietary phototoxin andd protoporphyria Johann W. Jonker*, Marije Buitelaar*. Els Wagenaar*, Martin A. van der Valkf, George L. Scheffer', Rik J. Scheper4, Torstenn Plösch5, Folkert Kuipers1, Ronald P. J. Oude Elferink1, Hilde Rosing , Jos H. Beijnen, and Alfred H. Schinkel*** Divisionss of * Experimental Therapy and 'Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; tt of Pathology, Free University Hospital, 1081 HV Amsterdam, The Netherlands; ^Center for Liver, Digestive, and Metabolic Diseases, Laboratoryy of Pediatrics, University Hoipital Groningen, 9713 GZ Groningen, The Netherlands; 'Laboratory of Experimental Hematology, Academicc Medical Center, 1105 AZ Amsterdam, The Netherlands; and Department of Pharmacy and Pharmacology, Slotervaart Hoipital,, 1066 EC Amsterdam, The Netherlands Communicatedd by P. Borst, The Netherlands Cancer Institute, Amsterdam, The Netherlands, October 8, 2002 (received for review September 10, 2002) Thee breast cancer resistance protein (BCRP ABCG2) is a member of logicallyy important in processes involving handling of porphy- thee ATP-binding cassette family of drug transporters and confers rins,, and we expect that a partial or complete deficiency for resistancee to various anticancer drugs. We show here that mice BCRPP may contribute to several porphyrin-related phototoxici- tackingg Bcrpl ..Abcg2 become extremely sensitive to the dietary tiess in humans and animals. chlorophyll-breakdownn product pheophorbide a, resulting in se- vere,, sometimes lethal phototoxic lesions on light-exposed skin. Materialss and Methods Pheophorbidee a occurs in various plant-derived foods and food Animals.. Mice were housed and handled according to institu- supplements.. Bcrpl transports pheophorbide a and is highly effi- tionall guidelines complying with Dutch legislation. Animals used cientt in limiting its uptake from ingested food. Bcrpl'- mice also inn this study were Bcrpl " and wild-type mice of a comparable displayedd a previously unknown type of protoporphyria. Erythro- geneticc background (FVB or mixed 129/Ola and FVB) between cytee levels of the heme precursor and phototoxin protoporphyrin 99 and 14 weeks of age. Animals were kept in a temperature- IX,, which is structurally related to pheophorbide a, were increased controlledd environment with a 12-h light/12-h dark cycle. They 10-fold.. Transplantation with wild-type bone marrow cured the receivedd a standard (AM-II) or semisynthetic (reference protoporphyriaa and reduced the phototoxin sensitivity of Bcrp1'~ 4068.02)) diet (Hope Farms, Woerden, The Netherlands) and mice.. These results indicate that humans or animals with low or acidifiedd water ad libitum. absentt BCRP activity may be at increased risk for developing protoporphyriaa and diet-dependent phototoxicity and provide a Materials.. Topotecan and [14C]topotecan [56 Ci/mol (1 Ci = 37 strikingg illustration of the importance of drug transporters in GBq))) were from GlaxoSmith Kline (King of Prussia, PA). protectionn from toxicity of normal food constituents. Pheophorbidee a was from Frontier Scientific/Porphyrin Prod- uctss (Logan, UT). emberss of the ATP-binding cassette (ABC) family of drug - - M transporterss actively export many drugs and toxins from Generationn of Bcrpl ' Mice. By using Bcrpl cDNA probes, a cells.. Their presence at strategic sites in the body such as the 129/Olaa mouse genomic sequence containing exons 1-8 of intestine,, blood-brain barrier, and placenta protects the organ- BcrplBcrpl was identified. A 5.1-kb fragment containing exons 3-6, ismm by limiting the systemic penetration and tissue toxicity of encodingg most of the ATP-binding domain, was deleted and xenotoxinss {1-3). The breast cancer resistance protein (BCRP/ replacedd with a 1.8-kb pgk-hygnt cassette in reverse-transcrip- ABCG2)) and its mouse homologue Bcrpl transport various tionall orientation. Electroporation and selection for recombi- anticancerr drugs including topotecan, mitoxantrone and doxo- nantt E14 embryonic stem cells was done as described (7), Of 161 rubicin,, thus causing multidrug resistance in cancer cells (3). We hygromycin-resistantt clones, 18 were targeted correctly as con- previouslyy found that application of BCRP inhibitors to mice firmedd by Southern analysis of .Sea I-digested genomic DNA with enhancedd the oral uptake and fetal penetration of topotecan, 3'' and 5' Bcrpl probes (Fig. \a). The absence of additional suggestingg that Bcrpl provides an efficient pharmacologic bar- pgk-hy^ropgk-hy^ro cassettes inserted elsewhere in the genome was con- rierr at these sites (4). Coadministration of BCRP inhibitors has firmedd by hybridization with a hygro-specific probe. Chimeric alsoo been tested in patients for its ability to improve anticancer micee were generated by microinjection of two independently chemotherapyy by enhancing oral uptake and possibly tumor targetedd embryonic stem cell clones into blastocysts. Chimeric penetrationn of BCRP substrate drugs. The first results are offspringg were backcrossed to FVB mice. By using this approach, promising,, but they also revealed unanticipated toxicity (5). It twoo independent Bcrpl' mouse lines were established. thuss is important to establish the risks associated with chronic inhibitionn of BCRP. Clinicall Chemical Analysis of Plasma. Standard clinical chemistry Too study the physiological and pharmacological functions of analysess on plasma were performed on a Hitachi 911 analyzer to BCRP,, we generated Bcrpl knockout mice. Absence of Bcrpl determinee levels of bilirubin, alkaline phosphatase, aspartate aminotransferase,, alanine aminotransferase, lactate dehydroge- resultedd in a striking sensitivity to the dietary chlorophyll : catabolitee pheophorbide a, which made these mice extremely nase,, creatinine, urea, Na'. K', Ca ', Ci , phosphate, total photosensitive.. Moreover, Bcrpl knockout mice displayed a protein,, and albumin. previouslyy uncharacterized type of protoporphyria, a group of metabolicc disorders frequently associated with skin photosensi- Abbreviations.. ABC, ATP-t.,nding cassette. BCRP ABCC2. breast cancer resistance protein. tivityy in patients (6). Pheophorbide a and protoporphyrin are Bcrpll Abtgi. murine BCRP; PPIX. protoporphyrin IX structurallyy related and belong to the porphyrins, a broad class ** *To whom correspondence should be addressed at. Division of Experimental Therapy. The off molecules that include the "pigments of life": chlorophyll, Netherlandss Cancer Institute. Presmanlaan 121. 10*6 CX Amsterdam. The Netherlands heme,, and cobalamin (6). Our data show that BCRP is physio- E-mail:: iKhinkeienkinl. 59 9 ChapterChapter 4 tionn of the fusion protein, immunization of rats, and fusion ee allele nn 1 2 3 4 5 protocolss were as described (10, 11). Results are shown for mAbb BXP-9 or BXP-53. which worked well on immunoblots +33 1 'fii, andd in immunohistochemistry. Westernn Analysis. Crude membrane fractions from tissues were preparedd as described (12). Western blotting was performed as describedd (7). Blots were probed with mAb BXP-9 (1:10). mAb bindingg was detected by using peroxidase-conjugated rabbit anti-ratt IgG (1:1.000. DAKO). Histologicall Analysis and Immunohistochemistry. Tissues were fixed inn 4% phosphate-buffered formalin, embedded in paraffin, sectionedd at 4 p.m, and stained with hematoxylin and eosin accordingg to standard procedures. For immunohistochemistry. tissuess were deparaffinized in xylene and rehydrated. Endoge- nouss peroxidase activity was blocked by using 3% (vol/vol) H2O2 inn methanol for 10 min. Before staining, paraffin sections were pretreatedd by heat-induced epitope retrieval. Slides were incu- batedd with 5T normal goat serum/PBS for 30 min,
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