Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists.
Breast cancer resistance protein (BCRP/ABCG2) is known to actively transport various anticancer drugs and to restrict the uptake of the food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine from the gut lumen. The present study reveals that BCRP is involved in the transport of phase-2 metabolites of the carcinogen benzo[a]pyrene (BP) in the human intestinal cell line Caco-2. Treatment with the selective BCRP inhibitor Ko 143 (5 microM) inhibited the apical transport of BP-3-sulfate (BP3S) to 83% of control levels in TC7 cells and to 64% of control levels in Caco-2 cells. The apical transport of BP-3-glucuronide was inhibited by Ko 143 to 76% of control levels in TC7 cells. Furthermore, the expression of BCRP is most likely aryl hydrocarbon receptor (AhR) dependent, as treatment of Caco-2 cells with known AhR agonists including 2,3,7,8-tetrachlorodibenzo-p-dioxin, BP, indolo[3,2-b]carbazole and benzo[k]fluoranthene increased both mRNA and protein levels of BCRP. Induced BCRP protein was found to be functionally active, since pre-treatment of TC7 cells with oltipraz, indolo[3,2-b]carbazole or benzo[k]fluoranthene increased the amount of apically transported BP3S to as much as 180% of that in the controls. The induction of BCRP (mRNA and protein expression) by indolo[3,2-b]carbazole was inhibited in Caco-2 cells by co-incubation with the AhR antagonist PD98059 (2'-amino-3'-methoxyflavone). In summary, this study provides strong evidence that BCRP is an important part of the intestinal barrier protecting the body from food-associated contaminants such as the carcinogen BP.
Ebert
Bettina
B
Institute for Food Toxicology, University of Veterinary Medicine Hannover, Foundation, Bischofsholern Damm 15/115, 30173 Hannover, Germany.
Seidel
Albrecht
A
Lampen
Alfonso
A
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D013871:Thiones; D013876:Thiophenes
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009363:Neoplasm Proteins; D000072317:Polychlorinated Dibenzodioxins; D011719:Pyrazines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D013871:Thiones; D013876:Thiophenes; D001564:Benzo(a)pyrene; C026209:oltipraz; D012110:Reserpine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one