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

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dc.authoridSelvi Durmuş Erim / 0000-0003-3792-1607
dc.authorscopusidSelvi Durmuş Erim / 49060997200
dc.authorwosidSelvi Durmuş Erim / J-2075-2018
dc.contributor.authorDurmuş Erim, Selvi
dc.contributor.authorvan der Valk, M.
dc.contributor.authorTeunissen, S. F.
dc.contributor.authorSong, J. Y.
dc.contributor.authorWagenaar, E.
dc.contributor.authorBeijnen, J. H.
dc.contributor.authorSchinkel, A. H.
dc.date.accessioned2020-08-30T20:06:55Z
dc.date.available2020-08-30T20:06:55Z
dc.date.issued2019
dc.departmentİstinye Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümüen_US
dc.description.abstract2-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.en_US
dc.identifier.citationDurmus, S., van der Valk, M., Teunissen, S. F., Song, J. Y., Wagenaar, E., Beijnen, J. H., & Schinkel, A. H. (2019). ABC transporters Mdr1a/1b, Bcrp1, Mrp2 and Mrp3 determine the sensitivity to PhIP/DSS-induced colon carcinogenesis and inflammation. Archives of toxicology, 93(3), 775-790.en_US
dc.identifier.doi10.1007/s00204-019-02394-wen_US
dc.identifier.endpage790en_US
dc.identifier.issn0340-5761en_US
dc.identifier.issn1432-0738en_US
dc.identifier.issue3en_US
dc.identifier.pmid30701287en_US
dc.identifier.scopus2-s2.0-85063998276en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage775en_US
dc.identifier.urihttps://doi.org/10.1007/s00204-019-02394-w
dc.identifier.urihttps://hdl.handle.net/20.500.12713/655
dc.identifier.volume93en_US
dc.identifier.wosWOS:000463730100016en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.institutionauthorDurmuş Erim, Selvien_US
dc.language.isoenen_US
dc.publisherSpringer Heidelbergen_US
dc.relation.ispartofArchives of Toxicologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectAbc Transportersen_US
dc.subjectPhipen_US
dc.subjectDssen_US
dc.subjectColon Canceren_US
dc.subjectCarcinogenesisen_US
dc.subjectInflammationen_US
dc.titleABC transporters Mdr1a/1b, Bcrp1, Mrp2 and Mrp3 determine the sensitivity to PhIP/DSS-induced colon carcinogenesis and inflammationen_US
dc.typeArticleen_US

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