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ABC transporters Mdr1a/1b, Bcrp1, Mrp2 and Mrp3 determine the sensitivity to PhIP/DSS-induced colon carcinogenesis and inflammation

  • Genotoxicity and Carcinogenicity
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Abstract

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is an abundant dietary carcinogen, formed during high-temperature cooking of meat. In this study, we investigated whether clinically relevant ATP-binding cassette (ABC) efflux transporters can modulate PhIP-induced colorectal carcinogenesis in vivo using wild-type (WT), Bcrp1−/−; Mrp2−/−; Mrp3−/− and Bcrp1−/−; Mdr1a/b−/−; Mrp2−/− mice. We used a physiological mouse model of colorectal cancer; a combination of a single high-dose oral PhIP administration (200 mg/kg), followed by administering a colonic inflammatory agent, dextran sodium sulfate (DSS), in drinking water for 7 days. Pilot experiments showed that both knockout strains were more sensitive to DSS-induced colitis compared to WT mice. Lack of these transporters in mice also led to clearly altered disposition of activated PhIP metabolites after a high-dose oral PhIP administration. The results suggest that Mdr1a/1b, Bcrp1 and Mrp2 contributed to biliary excretion and Mrp3 to sinusoidal secretion of the pre-carcinogenic metabolite N2-OH-PhIP. The levels of a genotoxicity marker, PhIP-5-sulphate, were at least 4- and 17-fold reduced in the intestinal tissue and intestinal content of both knockout strains compared to WT mice. In line with these findings, the level of colon carcinogenesis was reduced by two- to four-fold in both knockout strains compared to WT mice when PhIP and DSS treatments were combined. Thus, perhaps counterintuitively, reduced activity of these ABC transporters may in part protect from PhIP-induced colon carcinogenesis. Collectively, these data suggest that ABC transporters are important in protecting the body from inflammatory agents such as DSS, in the disposition of carcinogenic metabolites, and in determining the sensitivity to dietary PhIP-induced carcinogenesis.

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Acknowledgements

We thank Dr. Michael Hauptmann, Dr. Katarzyna Jozwiak and Mr. John Zavrakidis for the statistical support, and Dr. Seng Chuan Tang and Dr. Dilek Iusuf for occasional technical support in this project.

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Authors and Affiliations

  1. Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    S. Durmus, E. Wagenaar & A. H. Schinkel

  2. Department of Medical Biochemistry, Faculty of Medicine, Istinye University, Istanbul, Turkey

    S. Durmus

  3. Department of Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    M. van der Valk & J. Y. Song

  4. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    S. F. Teunissen & J. H. Beijnen

  5. Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    J. H. Beijnen

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  1. S. Durmus
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  2. M. van der Valk
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  3. S. F. Teunissen
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  4. J. Y. Song
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  5. E. Wagenaar
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  6. J. H. Beijnen
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  7. A. H. Schinkel
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Correspondence to A. H. Schinkel.

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This project was funded by internal funding from the Netherlands Cancer Institute. The authors declare that they have no conflict of interest.

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Durmus, S., van der Valk, M., Teunissen, S.F. et al. ABC transporters Mdr1a/1b, Bcrp1, Mrp2 and Mrp3 determine the sensitivity to PhIP/DSS-induced colon carcinogenesis and inflammation. Arch Toxicol 93, 775–790 (2019). https://doi.org/10.1007/s00204-019-02394-w

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