Carcinogenesis Advance Access published online on May 25, 2005
Carcinogenesis, doi:10.1093/carcin/bgi139
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1 Institute for Food Toxicology, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Germany
* To whom correspondence should be addressed. 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 as180% 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.
Received January 27, 2005
Revised May 20, 2005
Accepted May 22, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists
2 Biochemical Institute for Environmental Carcinogens, Prof. Dr. Gernot Grimmer Foundation, 22927 Grosshansdorf, Germany
Alfonso Lampen, E-mail: Alfonso.Lampen{at}tiho-hannover.de
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