Pharmaceutics, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Drug Metab Dispos. 2012 Mar;40(3):579-87. doi: 10.1124/dmd.111.043455. Epub 2011 Dec 20.
Single-walled carbon nanotubes (SWCNTs) have attracted attention for biomedical and biotechnological applications, such as drug delivery. However, there are concerns about the safety of SWCNTs for use in humans. To investigate the potential use of SWCNTs for targeted drug delivery to the lung, we examined their effect on drug-metabolizing enzymes in primary normal human bronchial epithelial (NHBE) cells from two donors and the lung carcinoma A549 cell line. Exposure of NHBE and A549 cells to SWCNTs dysregulated some of the important drug-metabolizing enzymes expressed in the human respiratory organs. Exposure of NHBE cells to SWCNTs for 24 h had a pronounced effect on expression of CYP1A1 and CYP1B1 mRNAs, which were reduced to less than 1% of control cells. These effects were also observed in A549 cells. Exposure of A549, HepG2 hepatic carcinoma cells, and MCF-7 breast carcinoma cells to tetrachlorodibenzo-p-dioxin induced the expression and enzymatic activity of CYP1A1 and CYP1B1, which were also suppressed by SWCNTs, suggesting that SWCNTs down-regulated both basal and induced CYP1A1 and CYP1B1 activities. Chromatin immunoprecipitation assays revealed that the down-regulatory effect of SWCNTs may be due to inhibition of activated aryl hydrocarbon receptor binding to the enhancer regions of the CYP1A1 and CYP1B1 genes. Down-regulation of CYP1A1 and CYP1B1 genes by SWCNTs may affect the defense mechanisms by reducing procarcinogen bioactivation in the human lung.
单壁碳纳米管（SWCNTs）在生物医药和生物技术应用方面引起了关注，例如药物输送。然而，人们对 SWCNTs 在人类中的使用安全性存在担忧。为了研究 SWCNTs 用于靶向肺内药物输送的潜力，我们研究了它们对来自两位供体的原代正常人类支气管上皮（NHBE）细胞和肺腺癌 A549 细胞系中药物代谢酶的影响。暴露于 SWCNTs 会使 NHBE 和 A549 细胞中的一些重要的人呼吸器官中表达的药物代谢酶失调。NHBE 细胞暴露于 SWCNTs 24 小时后，CYP1A1 和 CYP1B1 mRNA 的表达明显下调，降至对照细胞的不到 1%。在 A549 细胞中也观察到了这些影响。暴露于四氯二苯并对二恶英的 A549、HepG2 肝癌细胞和 MCF-7 乳腺癌细胞诱导了 CYP1A1 和 CYP1B1 的表达和酶活性，这些活性也被 SWCNTs 抑制，表明 SWCNTs 下调了基础和诱导的 CYP1A1 和 CYP1B1 活性。染色质免疫沉淀分析表明，SWCNTs 的下调作用可能是由于抑制了激活的芳烃受体与 CYP1A1 和 CYP1B1 基因的增强子区域结合。SWCNTs 下调 CYP1A1 和 CYP1B1 基因可能会影响人体肺部的前致癌物生物激活，从而影响防御机制。
