title: Downregulation of breast cancer resistance protein in colon adenomas reduces cellular xenobiotic resistance and leads to accumulation of a food-derived carcinogen.
abstract: Several molecular changes in colorectal adenomas provide the basis of the adenoma-carcinoma sequence. We investigated the expression of xenobiotic ATP-binding cassette (ABC) transporters in humans and in ApcMin mice and conducted functional studies estimating the importance of the expression changes. Twenty-nine adenomas from 21 patients and eight adenomas from four ApcMin mice were analyzed using Western blotting and quantitative Real-time polymerase chain reaction (RT-PCR). Adjacent healthy tissue served as control for each polyp. Breast cancer resistance protein (BCRP) was significantly downregulated in human colorectal adenomas (to 28 ± 35% of adjacent healthy tissue). This was in line with data from ApcMin mice adenomas, where downregulation was significant as well (to 58 ± 34%). In parallel, quantitative RT-PCR showed BCRP mRNA downregulation in human adenomas (to 17 ± 31%). Basal multidrug resistance-associated protein 2 expression was low and did not change in adenomas; multidrug resistance transporter 1 expression also did not differ between adenomas and healthy tissue. In a functional study, ApcMin mice received radioactively labelled 2-amino-1-methyl-6-phenylimidazo[4,5-β] pyridine (PhIP), a food colon carcinogen and substrate of BCRP, by oral gavage with analysis of PhIP accumulation and DNA adduct formation 48 hr later. In this setting, we could demonstrate a higher carcinogen concentration in adenomas of ApcMin mice (181 ± 113% of normal tissue) including immunohistochemical detection of PhIP-DNA adducts. We conclude that significant transcriptional downregulation of BCRP/Bcrp leads to higher carcinogen concentrations in colorectal adenomas of mice and men. This might promote the adenoma-carcinoma sequence by higher genotoxic effects. The results indicate a possible role of transporter deficiencies in susceptibility for colon carcinoma.
authors.affiliation: Department of Gastroenterology and Hepatology, Aachen University, Aachen, Germany. dietrich@bethlehem.de
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Dietrich
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Vehr
authors.forename: Ina V
authors.initials: IV
authors.lastname: Martin
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Timo
authors.initials: T
authors.lastname: Rath
authors.forename: Elke
authors.initials: E
authors.lastname: Roeb
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmitt
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000236:Adenoma / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000378:metabolism*; D018736:DNA Adducts / Q000032:analysis; D015536:Down-Regulation; D005260:Female; D005502:Food; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008297:Male; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015262:Xenobiotics
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D015262:Xenobiotics; C116614:ABCG2 protein, human; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine