Increased Bioavailability of the Food-Derived Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in MRP2-Deficient Rats

  1. Christoph G. Dietrich1,1,
  2. D. Rudi de Waart1,
  3. Roel Ottenhoff1,
  4. Ivo G. Schoots2 and
  5. Ronald P. J. Oude Elferink1
  1. 1Laboratory of Experimental Hepatology, Department of Gastroenterology (C.G.D., D.R.W., R.O., R.P.J.O.) and 2Surgical Laboratory, Department of Surgery (I.G.S.), Academic Medical Center, Amsterdam, The Netherlands

    Abstract

    MRP2 is an apical transporter expressed in hepatocytes and the epithelial cells of the small intestine and kidney proximal tubule. It extrudes organic anions, conjugated compounds, and some uncharged amphipaths. We studied the transport of an abundant food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in vitro, using an MRP2 transfected epithelial cell line (MDCK II) and intestinal explants from Wistar and MRP2-deficient TR− rats in Ussing chambers. In the experiments with the transfected cell line, we could demonstrate more than 3-fold higher transport from basolateral to apical than vice versa, whereas the transport in the parent cell line was equal in both directions. These results were confirmed in studies using isolated pieces of small intestine from Wistar and TR− rats in the Ussing chamber. Subsequent in vivo experiments demonstrated that after oral administration, absorption of PhIP was 2-fold higher in the TR− rat than in the Wistar rat. Consequently, PhIP tissue levels in several organs (liver, kidney, lung, and colon) were 1.7- to 4-fold higher 48 h after oral administration. MRP2 mediated transport of unchanged PhIP probably involves intracellular GSH, because GSH depletion by BSO-treatment in Wistar rats reduced intestinal secretion in the Ussing chamber to the same level as in TR− rats. In accordance, BSO treatment increased oral bioavailability in intact Wistar rats. This study shows for the first time that MRP2-mediated extrusion reduces oral bioavailability of a xenobiotic and protects against an abundant food-derived carcinogen.

    Footnotes

    • Send reprint requests to: R. P. J. Oude Elferink, Ph.D., Lab. of Experimental Hepatology, Dept. of Gastroenterology, Academic Medical Center, F0–116, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. E-mail: r.p.oude-elferink{at}amc.uva.nl

    • ↵1 Future address: Med. Klinik III, Universitätsklinikum der RWTH, Pauwelsstr. 30, 52057 Aachen, Germany.

    • This study was supported in part by a grant from the START fund (92/98, Technical University of Aachen, Germany) (C.G.D.) and by Grant UVA 2001-2555 from the Dutch Cancer Foundation (R.P.J.O.).

    • Abbreviations:
      MDR
      multidrug resistance transporter
      MRP
      multidrug resistance protein
      PhIP
      2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
      HPLC
      high performance liquid chromatography
      BSO
      buthionine-sulfoximine
      GSH
      glutathione
      • Received September 26, 2000.
      • Accepted December 27, 2000.
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    1. Molecular Pharmacology May 1, 2001 vol. 59 no. 5 974-980
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