Low-levels of graphene inhibit cellular xenobiotic defense system mediated by efflux transporters Abstract
作者单位：State Key Laboratory of Pollution Control and Resource Reuse School of the Environment Nanjing University Bodega Marine Laboratory University of CaliforniaDavis California USA Departments of Environmental Toxicology and Nutrition University of CaliforniaDavis California USA
会议名称：《全国环境纳米技术及生物效应学术研讨会》
会议日期：2016年
学科分类：100405[医学-卫生毒理学] 081702[工学-化学工艺] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 08[工学] 0817[工学-化学工程与技术] 10[医学]
基 金：supported by Natural Science Foundation of Jiangsu Province (BK20131270 and BK20130557) National Natural Science Foundation (21577061) supported by the National Science Foundation and the Environmental Protection Agency under Cooperative Agreement Number DBI-0830117 and DBI-1266377
关 键 词：Graphene ABC transporter Cytotoxicity Chemosensitizer
摘 要：Dose is one of the most important factors of nanomaterial（NM） toxicity. Low levels of NMs are considered to be safe[1]. In this study, we analyzed the potential toxicity of Graphene at relatively low concentration on plasma membrane ABC transporter activity of Human cell line HepG2. In the cell membrane, ABC transporters are common and are known to play a crucial role in multidrug resistance（MDR） [2, 3], where they function as efflux pumps and are responsible for chemotherapeutic drug resistance in cancer cells. ABC transporters can also pump xenobiotics out of the cell using an ATPdependent mechanism, thus reducing potential toxic effects. The results showed that Graphene（0.5 μg/mL） did not decrease cell viability, generate reactive oxygen species（ROS） and cause cell apoptosis. However, Graphene at non-toxic concentration could increase Calcein-AM（CAM, an indicator of membrane ABC transporter activities） accumulation, indicating inhibition of ABC transporters’ activities. This inhibition could be observed even at 0.005μg/mL, which is 100-times and lower than its lowest toxic concentration from cytotoxicity experiments. The inhibition of ABC transporters significantly sensitized the toxicity of paraquat, a toxic and widely used herbicide and a known substrate of ABC transporters. The potential mechanism of inhibition of membrane transporter activities caused by Graphene was further analyzed by gene expression, protein expression and membrane integrity and function. Based on above results, we assume that Graphene can damage cell membrane functions, and thus causing an inhibition of potentially all plasma membrane transporter（P-gp/MRP/BCRP） activity. This study shows the amplification of environmental effects of Graphene at non-toxic concentrations, which could significantly cause the inhibition of ABC transporters’ activities.