Breast cancer resistance protein (Bcrp1/Abcg2) reduces systemic exposure of the dietary carcinogens aflatoxin B1, IQ and Trp-P-1 but also mediates their secretion into breast milk.
Breast cancer resistance protein (Bcrp1/Abcg2) reduces systemic exposure of the dietary carcinogens aflatoxin B1, IQ and Trp-P-1 but also mediates their secretion into breast milk.
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乳腺癌抗性蛋白 (Bcrp1/Abcg2) 可减少膳食致癌物黄曲霉毒素 B1、IQ 和 Trp-P-1 的全身暴露，同时还能介导它们分泌到母乳中。
DOI：
10.1093/carcin/bgi176
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发表时间：
2006
期刊：
影响因子：
4.7
通讯作者：
A. Schinkel
中科院分区：
文献类型：
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作者：
A. V. van Herwaarden;E. Wagenaar;Barbara N Karnekamp;G. Merino;J. Jonker;A. Schinkel
乳腺癌抵抗蛋白（BCRP/ABCG2）通常通过减少肠道对各种环境和饮食异种毒素的净吸收，并通过增加肝胆、肠道和肾脏对其的清除，保护身体免受各种环境和饮食异种毒素的侵害。BCRP在小鼠泌乳乳腺中也有高表达，在奶牛和人类中也有保守表达。因此，BCRP底物可以分泌到牛奶中。我们调查了不同种类的膳食致癌物是否为Bcrp1/BCRP的底物，以及对全身暴露和母乳污染的影响。通过极化细胞系，我们发现Bcrp1转运杂环胺2-氨基-3-甲基咪唑[4,5-f]喹啉（IQ）和3-氨基-1,4-二甲基- 5h -吡啶[4,3-b]吲哚（Trp-P-1）和强效人类肝癌致癌物黄曲霉毒素B1，并将它们的细胞积累减少10倍。体内药代动力学研究表明，口服和静脉给药后，野生型小鼠[14C]IQ、[14C]Trp-P-1和[3H]黄曲霉毒素B1血浆水平明显低于Bcrp1-/-小鼠，表明Bcrp1限制了这些致癌物的全身暴露。此外，Bcrp1介导[14C]IQ、[14C]Trp-P-1和[3H]黄曲霉毒素向乳中的转移，与Bcrp1-/-小鼠相比，泌乳野生型小鼠的乳浆比分别高出3.4+/-0.6、2.6+/-0.3和3.8+/-0.5倍。因此，我们已经确定Bcrp1/BCRP是杂环胺和黄曲霉毒素转移到牛奶中的分子机制之一，从而对母乳喂养的婴儿和乳制品消费者构成健康风险。矛盾的是，Bcrp1/BCRP在暴露于膳食致癌物方面似乎既有保护作用，也有不利作用。
The breast cancer resistance protein (BCRP/ABCG2) usually protects the body from a wide variety of environmental and dietary xenotoxins by reducing their net uptake from intestine and by increasing their hepatobiliary, intestinal and renal elimination. BCRP is also highly expressed in lactating mammary glands in mice, and this expression is conserved in cows and humans. As a result, BCRP substrates can be secreted into milk. We investigated whether different classes of dietary carcinogens are substrates of Bcrp1/BCRP and the implications for systemic exposure and breast milk contamination. Using polarized cell lines, we found that Bcrp1 transports the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and the potent human hepatocarcinogen aflatoxin B1, and decreases their cellular accumulation up to 10-fold. In vivo pharmacokinetic studies showed that [14C]IQ, [14C]Trp-P-1 and [3H]aflatoxin B1 plasma levels were substantially lower in wild-type compared with Bcrp1-/- mice, after both oral and intravenous administration, demonstrating that Bcrp1 restricts systemic exposure to these carcinogens. Moreover, Bcrp1 mediates transfer of [14C]IQ, [14C]Trp-P-1 and [3H]aflatoxin into milk, with 3.4+/-0.6, 2.6+/-0.3 and 3.8+/-0.5-fold higher milk to plasma ratios, respectively, in lactating wild-type versus Bcrp1-/- mice. We have thus identified Bcrp1/BCRP as one of the molecular mechanisms by which heterocyclic amines and aflatoxin are transferred into milk, thereby posing a health risk to breast-fed infants and dairy consumers. Paradoxically, Bcrp1/BCRP appears to have both protective and adverse roles with respect to exposure to dietary carcinogens.
影响因子：
4.7
作者：
LAYTON, DW;BOGEN, KT;FELTON, JS
通讯作者：
FELTON, JS
DOI：
10.1097/00008571-200301000-00004
发表时间：
2003-01-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Zamber, CP;Lamba, JK;Schuetz, EG
通讯作者：
Schuetz, EG