Ebert Bettina, Seidel Albrecht, Lampen Alfonso
Institute for Food Toxicology, University of Veterinary Medicine Hannover, Foundation, Bischofsholern Damm 15/115, 30173 Hannover, Germany.
Carcinogenesis. 2005 Oct;26(10):1754-63. doi: 10.1093/carcin/bgi139. Epub 2005 May 25.
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.
乳腺癌耐药蛋白（BCRP/ABCG2）可主动转运多种抗癌药物，并限制肠道腔内食物致癌物2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶的摄取。本研究表明，BCRP参与了致癌物苯并[a]芘（BP）的Ⅱ相代谢产物在人肠上皮细胞系Caco-2中的转运。用选择性BCRP抑制剂Ko 143（5微摩尔）处理，可将TC7细胞中BP-3-硫酸盐（BP3S）的顶端转运抑制至对照水平的83%，将Caco-2细胞中BP-3-硫酸盐的顶端转运抑制至对照水平的64%。Ko 143将TC7细胞中BP-3-葡萄糖醛酸苷的顶端转运抑制至对照水平的76%。此外，BCRP的表达很可能依赖芳烃受体（AhR），因为用包括2,3,7,8-四氯二苯并对二恶英、BP、吲哚并[3,2-b]咔唑和苯并[k]荧蒽在内的已知AhR激动剂处理Caco-2细胞，可增加BCRP的mRNA和蛋白水平。发现诱导产生的BCRP蛋白具有功能活性，因为用奥替普拉、吲哚并[3,2-b]咔唑或苯并[k]荧蒽预处理TC7细胞，可使顶端转运的BP3S量增加至对照细胞的180%。在Caco-2细胞中，与AhR拮抗剂PD98059（2'-氨基-3'-甲氧基黄酮）共同孵育可抑制吲哚并[3,2-b]咔唑对BCRP（mRNA和蛋白表达）的诱导。总之，本研究提供了有力证据，表明BCRP是肠道屏障的重要组成部分，可保护机体免受食物相关污染物如致癌物BP的侵害。
