title: Low levels of graphene and graphene oxide inhibit cellular xenobiotic defense system mediated by efflux transporters.
abstract: Low levels of graphene and graphene oxide (GO) are considered to be environmentally safe. In this study, we analyzed the potential effects of graphene and GO at relatively low concentrations on cellular xenobiotic defense system mediated by efflux transporters. The results showed that graphene (<0.5 μg/mL) and GO (<20 μg/mL) did not decrease cell viability, generate reactive oxygen species, or disrupt mitochondrial function. However, graphene and GO at the nontoxic concentrations could increase calcein-AM (CAM, an indicator of membrane ATP-binding cassette (ABC) transporter) activity) accumulation, indicating inhibition of ABC transporters' efflux capabilities. This inhibition was observed even at 0.005 μg/mL graphene and 0.05 μg/mL GO, which are 100 times and 400 times lower than their lowest toxic concentration from cytotoxicity experiments, respectively. The inhibition of ABC transporters significantly increased the toxicity of paraquat and arsenic, known substrates of ABC transporters. The inhibition of ABC transporters was found to be based on graphene and GO damaging the plasma membrane structure and fluidity, thus altering functions of transmembrane ABC transporters. This study demonstrates that low levels of graphene and GO are not environmentally safe since they can significantly make cell more susceptible to other xenobiotics, and this chemosensitizing activity should be considered in the risk assessment of graphene and GO.
authors.affiliation: a State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment , Nanjing University , Nanjing , P.R. China .
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.affiliation: a State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment , Nanjing University , Nanjing , P.R. China .
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: a State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment , Nanjing University , Nanjing , P.R. China .|b Bodega Marine Laboratory, University of California , Davis , CA , USA , and.
authors.forename: Bing
authors.initials: B
authors.lastname: Wu
authors.affiliation: a State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment , Nanjing University , Nanjing , P.R. China .
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: a State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment , Nanjing University , Nanjing , P.R. China .
authors.forename: Haiyan
authors.initials: H
authors.lastname: Yu
authors.affiliation: a State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment , Nanjing University , Nanjing , P.R. China .
authors.forename: Xu-Xiang
authors.initials: XX
authors.lastname: Zhang
authors.affiliation: b Bodega Marine Laboratory, University of California , Davis , CA , USA , and.
authors.forename: Cristina
authors.initials: C
authors.lastname: Torres-Duarte
authors.affiliation: b Bodega Marine Laboratory, University of California , Davis , CA , USA , and.|c Departments of Environmental Toxicology and Nutrition , University of California , Davis , CA , USA.
authors.forename: Gary N
authors.initials: GN
authors.lastname: Cherr
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000737:chemistry / Q000378:metabolism; D006108:Graphite / Q000737:chemistry / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D010087:Oxides / Q000737:chemistry / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015262:Xenobiotics / Q000737:chemistry / Q000633:toxicity*
chemical_list: D018528:ATP-Binding Cassette Transporters; D005452:Fluoresceins; D010087:Oxides; D017382:Reactive Oxygen Species; D015262:Xenobiotics; C085925:calcein AM; D006108:Graphite; C007740:fluorexon
keywords: ABC transporter; HepG2; cytotoxicity; graphene; graphene oxide