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Molecular Pharmacology

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Research ArticleArticle

The Effect of Low pH on Breast Cancer Resistance Protein (ABCG2)-Mediated Transport of Methotrexate, 7-Hydroxymethotrexate, Methotrexate Diglutamate, Folic Acid, Mitoxantrone, Topotecan, and Resveratrol in In Vitro Drug Transport Models

Pauline Breedveld, Dick Pluim, Greta Cipriani, Femke Dahlhaus, Maria A. J. van Eijndhoven, Cornelia J. F. de Wolf, Annemieke Kuil, Jos H. Beijnen, George L. Scheffer, Gerrit Jansen, Piet Borst and Jan H. M. Schellens
Molecular Pharmacology January 2007, 71 (1) 240-249; DOI: https://doi.org/10.1124/mol.106.028167
Pauline Breedveld
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Dick Pluim
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Greta Cipriani
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Femke Dahlhaus
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Maria A. J. van Eijndhoven
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Cornelia J. F. de Wolf
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Annemieke Kuil
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Jos H. Beijnen
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George L. Scheffer
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Gerrit Jansen
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Piet Borst
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Jan H. M. Schellens
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Abstract

Some cellular uptake systems for (anti)folates function optimally at acidic pH. We have tested whether this also applies to efflux from cells by breast cancer resistance protein (BCRP; ABCG2), which has been reported to transport folic acid, methotrexate, and methotrexate di- and triglutamate at physiological pH. Using Spodoptera frugiperda-BCRP membrane vesicles, we showed that the ATP-dependent vesicular transport of 1 μM methotrexate by BCRP is 5-fold higher at pH 5.5 than at physiological pH. The transport of methotrexate was saturable at pH 5.5, with apparent Km and Vmax values of 1.3 ± 0.2 mM and 44 ± 2.5 nmol/mg of protein/min, respectively, but was linear with drug concentration at pH 7.3 up to 6 mM methotrexate. In contrast to recent reports, we did not detect transport of methotrexate diglutamate at physiological pH, but we did find transport at pH 5.5. We also found that 7-hydroxy-methotrexate, the major metabolite of methotrexate, is transported by BCRP both at physiological pH and (more efficiently) at low pH. The pH effect was also observed in intact BCRP-overexpressing cells: we found a 3-fold higher level of resistance to both methotrexate and the prototypical BCRP substrate mitoxantrone at pH 6.5 as at physiological pH. Furthermore, with MDCKII-BCRP monolayers, we found that resveratrol, which is a neutral compound at pH ≤ 7.4, is efficiently transported by BCRP at pH 6.0, whereas we did not detect active transport at pH 7.4. We conclude that BCRP transports substrate drugs more efficiently at low pH, independent of the dissociation status of the substrate.

Footnotes

  • This work has been presented previously in abstract form: Breedveld P, Pluim D, Cipriani G, Dahlhaus F, van Eijndhoven MAJ, Borst P, and Schellens JHM (2005) The effect of low pH on BCRP(ABCG2)-mediated transport of methotrexate, 7-hydroxymetotrexate, methotrexate diglutamate, folic acid and resveratrol in in vitro drug transport models. Proceedings of the American Association of Cancer Research LB-262.

  • ABBREVIATIONS: MTX, methotrexate; BCRP, breast cancer resistance protein; MRP, multidrug resistance-associated protein; 7-OH-MTX, 7-hydroxy-methotrexate; MTX-glu2, methotrexate diglutamate; Sf9, Spodoptera frugiperda; HPLC, high-performance liquid chromatography; LY335979, zosuquidar trihydrochloride; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; SN-38, 7-ethyl-10-hydroxycamptothecin; solution A, formic acid and acetonitrile 5%; solution B, formic acid and acetonitril 23%; Ko143, 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester.

    • Received June 25, 2006.
    • Accepted September 25, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (1)
Molecular Pharmacology
Vol. 71, Issue 1
1 Jan 2007
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The Effect of Low pH on Breast Cancer Resistance Protein (ABCG2)-Mediated Transport of Methotrexate, 7-Hydroxymethotrexate, Methotrexate Diglutamate, Folic Acid, Mitoxantrone, Topotecan, and Resveratrol in In Vitro Drug Transport Models
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Research ArticleArticle

The Effect of Low pH on Breast Cancer Resistance Protein (ABCG2)-Mediated Transport of Methotrexate, 7-Hydroxymethotrexate, Methotrexate Diglutamate, Folic Acid, Mitoxantrone, Topotecan, and Resveratrol in In Vitro Drug Transport Models

Pauline Breedveld, Dick Pluim, Greta Cipriani, Femke Dahlhaus, Maria A. J. van Eijndhoven, Cornelia J. F. de Wolf, Annemieke Kuil, Jos H. Beijnen, George L. Scheffer, Gerrit Jansen, Piet Borst and Jan H. M. Schellens
Molecular Pharmacology January 1, 2007, 71 (1) 240-249; DOI: https://doi.org/10.1124/mol.106.028167

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Research ArticleArticle

The Effect of Low pH on Breast Cancer Resistance Protein (ABCG2)-Mediated Transport of Methotrexate, 7-Hydroxymethotrexate, Methotrexate Diglutamate, Folic Acid, Mitoxantrone, Topotecan, and Resveratrol in In Vitro Drug Transport Models

Pauline Breedveld, Dick Pluim, Greta Cipriani, Femke Dahlhaus, Maria A. J. van Eijndhoven, Cornelia J. F. de Wolf, Annemieke Kuil, Jos H. Beijnen, George L. Scheffer, Gerrit Jansen, Piet Borst and Jan H. M. Schellens
Molecular Pharmacology January 1, 2007, 71 (1) 240-249; DOI: https://doi.org/10.1124/mol.106.028167
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