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      Nanostructures of diamond, graphene oxide and graphite inhibit CYP1A2, CYP2D6 and CYP3A4 enzymes and downregulate their genes in liver cells


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          Introduction and objective

          Currently, carbon nanostructures are vastly explored materials with potential for future employment in biomedicine. The possibility of employment of diamond nanoparticles (DN), graphene oxide (GO) or graphite nanoparticles (GN) for in vivo applications raises a question of their safety. Even though they do not induce a direct toxic effect, due to their unique properties, they can still interact with molecular pathways. The objective of this study was to assess if DN, GO and GN affect three isoforms of cytochrome P450 (CYP) enzymes, namely, CYP1A2, CYP2D6 and CYP3A4, expressed in the liver.


          Dose-dependent effect of the DN, GO and GN nanostructures on the catalytic activity of CYPs was examined using microsome-based model. Cytotoxicity of DN, GO and GN, as well as the influence of the nanostructures on mRNA expression of CYP genes and CYP-associated receptor genes were studied in vitro using HepG2 and HepaRG cell lines.


          All three nanostructures interacted with the CYP enzymes and inhibited their catalytic activity in microsomal-based models. CYP gene expression at the mRNA level was also downregulated in HepG2 and HepaRG cell lines. Among the three nanostructures, GO showed the most significant influence on the enzymes, while DN was the most inert.


          Our findings revealed that DN, GO and GN might interfere with xenobiotic and drug metabolism in the liver by interactions with CYP isoenzymes responsible for the process. Such results should be considered if DN, GO and GN are used in medical applications.

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          Most cited references 46

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          Interaction of nanoparticles with proteins: relation to bio-reactivity of the nanoparticle

          Interaction of nanoparticles with proteins is the basis of nanoparticle bio-reactivity. This interaction gives rise to the formation of a dynamic nanoparticle-protein corona. The protein corona may influence cellular uptake, inflammation, accumulation, degradation and clearance of the nanoparticles. Furthermore, the nanoparticle surface can induce conformational changes in adsorbed protein molecules which may affect the overall bio-reactivity of the nanoparticle. In depth understanding of such interactions can be directed towards generating bio-compatible nanomaterials with controlled surface characteristics in a biological environment. The main aim of this review is to summarise current knowledge on factors that influence nanoparticle-protein interactions and their implications on cellular uptake.
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            Cytochromes P450 and metabolism of xenobiotics.

            Cytochromes P450 (henceforth P450s) are involved in a variety of metabolic and biosynthetic processes. The number of known P450 enzymes exceeds 1000, while the endogenous substrates of most of them remain unknown. All P450 enzymes exhibit similarity in their structure and general mechanism of action; however, there are significant differences in the detailed function of individual enzymes as well as in the structures and properties of their active sites. This review discusses the properties of the most important P450 enzymes taking part in drug metabolism in humans. P450 3A4 is of paramount importance, because it is the most abundant P450 in the human liver and is known to metabolize the majority of drugs whose biotransformation is known. Genetically dependent variabilities of individual P450 activities and levels are described, documenting the importance of pharmacogenetics aimed at explaining differences in the response of the organism to various drugs.
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              The biomolecular corona is retained during nanoparticle uptake and protects the cells from the damage induced by cationic nanoparticles until degraded in the lysosomes.

              Nanoparticles have unique capacities of interacting with the cellular machinery and entering cells. To be able to exploit this potential, it is essential to understand what controls the interactions at the interface between nanoparticles and cells: it is now established that nanoparticles in biological media are covered by proteins and other biomolecules forming a "corona" on the nanoparticle surface, which confers a new identity to the nanoparticles. By labelling the proteins of the serum, using positively-charged polystyrene, we now show that this adsorbed layer is strong enough to be retained on the nanoparticles as they enter cells and is trafficked to the lysosomes on the nanoparticles. There, the corona is degraded and this is followed by lysosomal damage, leading to cytosolic release of lysosomal content, and ultimately apoptosis. Thus the corona protects the cells from the damage induced by the bare nanoparticle surface until enzymatically cleared in the lysosomes. This study investigates the effects of protein corona that normally forms on the surface of nanoparticles during in vivo use, describing the steps of intracellular processing of such particles, to enhance our understanding of how these particles interact with the cellular machinery. Copyright © 2013 Elsevier Inc. All rights reserved.

                Author and article information

                Int J Nanomedicine
                Int J Nanomedicine
                International Journal of Nanomedicine
                International Journal of Nanomedicine
                Dove Medical Press
                13 December 2018
                : 13
                : 8561-8575
                [1 ]Division of Nanobiotechnology, Warsaw University of Life Sciences, Warsaw, Poland
                [2 ]Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark, ach@ 123456sund.ku.dk
                Author notes
                Correspondence: André Chwalibog, Department of Veterinary and Animal Sciences, University of Copenhagen, Groennegaardsvej 3, 1870 Frederiksberg, Denmark, Tel +45 40 96 3573, Email ach@ 123456sund.ku.dk
                © 2018 Strojny et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Molecular medicine

                carbon nanostructures, nanoparticles, cytochrome p450, microsomes, liver


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