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.

• ABC transporter
• cytotoxicity
• graphene
• graphene oxide
• HepG2

Acknowledgements

The authors would like to acknowledge funding from the UC MEXUS-CONACyT Postdoctoral Research Fellowship Program (C. Torres Duarte).

Declaration of interest

This work was supported by Natural Science Foundation of Jiangsu Province (BK20131270 and BK20130557), National Natural Science Foundation of China (21577061 and 51208250), Specialized Research Fund for the Doctoral Program of Higher Education (20130091120012), Foundation of State Key Laboratory of Pollution Control and Resource Reuse. This research is also part of the University of California Center for the Environmental Implications of Nanotechnology (UC CEIN) and was supported by the National Science Foundation and the Environmental Protection Agency under Cooperative Agreement Number DBI-0830117 and DBI-1266377. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation or the Environmental Protection Agency. This work has not been subjected to EPA review and no official endorsement should be inferred.

Supplementary material available online