Polycyclic aromatic hydrocarbons in food--efflux of the conjugated biomarker 1-hydroxypyrene is mediated by Breast Cancer Resistance Protein (ABCG2) in human intestinal Caco-2 cells.
Polycyclic aromatic hydrocarbons in food--efflux of the conjugated biomarker 1-hydroxypyrene is mediated by Breast Cancer Resistance Protein (ABCG2) in human intestinal Caco-2 cells.
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DOI：
10.1016/j.fct.2013.10.007
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
S. Hessel;A. Lampen;A. Seidel
中科院分区：
文献类型：
--
作者：
S. Hessel;A. Lampen;A. Seidel
多环芳烃（PAHs）是众所周知的食品污染物，包括具有致癌特性的化合物。芘（PYR）是一种重要的非致癌性多环芳烃，因为其代谢产物经常被用作评估人类多环芳烃暴露的生物标志物。本研究首次采用高效液相色谱技术研究了PYR代谢产物在人小肠Caco-2细胞模型中的形成和转运。细胞色素P450单加氧酶形成的中间I相代谢物1-羟基芘随后通过II相酶与水溶性PYR 1-葡糖苷酸（次要代谢物）和PYR 1-硫酸盐（主要代谢物）结合。后者的形成由人磺基转移酶1A 1-Arg、1A 2-Arg 1、1A 3和1B 1介导。Caco-2单层实验显示，乳腺癌耐药蛋白（BCRP/ABCG 2）介导的两种偶联物的主要顶端转运。用几种芳烃受体（AhR）激动剂的额外治疗表明AhR驱动的PYR代谢酶和/或ABCG 2的诱导。总的来说，这项研究提供了先进的机械见解PYR的生物利用度，并强调了人类小肠上皮细胞的关键作用，食品中的污染物的首过代谢。
Polycyclic aromatic hydrocarbons (PAHs) are well-known food contaminants comprising compounds with carcinogenic properties. Pyrene (PYR) is an important non-carcinogenic PAH because its metabolites are frequently used as biomarkers to assess human PAH exposure. This study investigated for the first time the formation and transport of PYR metabolites in the human small intestinal Caco-2 cell model using HPLC technique. The intermediate phase I metabolite 1-hydroxypyrene formed by cytochrome P450 monooxygenases is subsequently conjugated by phase II enzymes to the water-soluble PYR 1-glucuronide as minor and PYR 1-sulfate as major metabolites. The formation of the latter is mediated by human sulfotransferases 1A1∗Arg, 1A2∗1, 1A3, and 1B1. Caco-2 monolayer experiments revealed a predominantly apical transport of both conjugates mediated by the breast cancer resistance protein (BCRP/ABCG2). Additional treatment with several aryl hydrocarbon receptor (AhR) agonists indicate an AhR-driven induction of PYR-metabolizing enzymes and/or ABCG2. Overall, this study provides advanced mechanistic insights into the bioavailability of PYR and underlines a key role of the human small intestinal epithelium for the first pass metabolism of contaminants in food.