Journal Article

Identification of BCRP as transporter of benzo[<i>a</i>]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists

Bettina Ebert, Albrecht Seidel and Alfonso Lampen

in Carcinogenesis

Volume 26, issue 10, pages 1754-1763
Published in print October 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI:
Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists

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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.

Keywords: 3-MC, 3-methylcholanthrene; ABC, ATP-binding cassette; AhR, aryl hydrocarbon receptor; B[k]F, benzo[k]fluoranthene; BCRP, breast cancer resistance protein; BP, benzo[a]pyrene; BP3G, BP-3-glucuronide; BP-3-OH, 3-hydroxybenzo[a]pyrene; BP3S, BP-3-sulfate; CYP, cytochrome P450; DMSO, dimethylsulfoxide; ICZ, indolo[3,2-b]carbazole; MRP, multidrug resistance-associated proteins; PAH, polycyclic aromatic hydrocarbons; PBS, phosphate-buffered saline; PD98059, 2′-amino-3′-methoxyflavone; P-gp, P-glycoprotein; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEER, transepithelial electrical resistance; UGT, UDP glucuronosyltransferases; α-NF, α-naphthoflavone; XME, xenobiotic-metabolizing enzymes

Journal Article.  8018 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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