Carcinogenesis Advance Access originally published online on May 25, 2005
Carcinogenesis 2005 26(10):1754-1763; doi:10.1093/carcin/bgi139
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Carcinogenesis vol.26 no.10 © Oxford University Press 2005; all rights reserved.
Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists
1 Institute for Food Toxicology, University of Veterinary Medicine Hannover, Foundation, Bischofsholern Damm 15/115, 30173 Hannover, Germany, 2 Biochemical Institute for Environmental Carcinogens, Prof. Dr Gernot Grimmer Foundation, Lurup 4, D-22927 Grosshansdorf, Germany and 3 Federal Institute for Risk Assessment (BfR), Thielallee 88-92, D-14195 Berlin, Germany
* To whom correspondence should be addressed Email: Alfonso.Lampen{at}tiho-hannover.de
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 µM) 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.
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