Federal Institute for Risk Assessment, Department of Food Safety, Thielallee 88-92, 14195 Berlin, Germany.
Toxicol Lett. 2010 Aug 16;197(2):151-5. doi: 10.1016/j.toxlet.2010.05.018. Epub 2010 Jun 1.
All-trans retinoic acid (atRA) is the most active metabolite of vitamin A. It is a ligand of retinoic acid receptors (RAR) as well as of retinoid X receptors (RXR) and effectively stimulates the RAR/RXR signalling pathway. In this study effects of atRA on the detoxification of the food contaminant benzo[a]pyrene (B[a]P) was elucidated by using the Caco-2 cell line as model system for the human small intestine. Caco-2 cells express a number of phase I and II xenobiotic-metabolising enzymes as well as several transport proteins of the ATP-binding cassette (ABC) superfamily. Pre-treatment of the cells with atRA resulted in enhanced apical excretion of B[a]P-3-sulfate, a phase II metabolite of B[a]P. Gene expression analysis revealed that the Breast Cancer Resistance Protein (BCRP), an ABC-transporter known to be involved in B[a]P-3-sulfate excretion, was strongly stimulated already at low concentrations of atRA. Furthermore co-incubation of the intestinal cell with RAR agonist and RXR agonist resulted in a strong additive induction of mRNA expression of BCRP. Thus, atRA was shown to induce BCRP gene expression probably via the RAR/RXR signalling pathway, resulting in effective removal of B[a]P metabolites from intestinal cells.
全反式视黄酸（atRA）是维生素 A 的最活跃代谢物。它是视黄酸受体（RAR）和视黄醇 X 受体（RXR）的配体，有效刺激 RAR/RXR 信号通路。在这项研究中，使用 Caco-2 细胞系作为人类小肠的模型系统，阐明了 atRA 对食品污染物苯并[a]芘（B[a]P）解毒的影响。Caco-2 细胞表达了许多 I 相和 II 相异生素代谢酶，以及 ABC 超家族的几种转运蛋白。用 atRA 预处理细胞会导致 B[a]P-3-硫酸盐（B[a]P 的 II 相代谢物）的顶端排泄增加。基因表达分析显示，乳腺癌耐药蛋白（BCRP），一种已知参与 B[a]P-3-硫酸盐排泄的 ABC 转运蛋白，在低浓度的 atRA 下就被强烈刺激。此外，将肠道细胞与 RAR 激动剂和 RXR 激动剂共同孵育会导致 BCRP mRNA 表达的强烈相加诱导。因此，atRA 可能通过 RAR/RXR 信号通路诱导 BCRP 基因表达，从而有效地将 B[a]P 代谢物从肠道细胞中去除。
