The effect of graphene oxide on signalling of xenobiotic receptors involved in biotransformation

Ženata, Ondřej; Vrzalová, Aneta; Bachleda, Petr; Janeckova, Jana; Panáček, Aleš; Kvı́tek, Libor; Vrzal, Radim

doi:10.1016/j.chemosphere.2020.126753

Cited by 8 publications

(12 citation statements)

References 39 publications

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“…Notably, Strojny et al reported that in HepaRG™ cells GO (50 μg/ml) significantly downregulated CAR and PXR ( Strojny et al, 2018 ), which are nuclear receptors acting as ligand (xenobiotic)-dependent, transcription regulators of a large part of phase-I, -II and -III executioners ( Evans and Mangelsdorf 2014 ). Analogously, using PHH as hepatic cell model, it has been reported GO (20 μg/ml) decreased PXR protein ( Ženata et al, 2020 ). In our cell model, we confirmed the GO-induced downregulation of PXR only by the highest concentration (80 μg/ml), while CAR resulted unaffected.…”

Section: Discussionmentioning

confidence: 86%

Sub-Lethal Concentrations of Graphene Oxide Trigger Acute-Phase Response and Impairment of Phase-I Xenobiotic Metabolism in Upcyte® Hepatocytes

Romaldini

Spanò

Catalano

et al. 2022

Front. Bioeng. Biotechnol.

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The impact of graphene oxide on hepatic functional cells represents a crucial evaluation step for its potential application in nanomedicine. Primary human hepatocytes are the gold standard for studying drug toxicity and metabolism; however, current technical limitations may slow down the large-scale diffusion of this cellular tool for in vitro investigations. To assess the potential hepatotoxicity of graphene oxide, we propose an alternative cell model, the second-generation upcyte® hepatocytes, which show metabolic and functional profiles akin to primary human hepatocytes. Cells were acutely exposed to sub-lethal concentrations of graphene oxide (≤80 μg/ml) for 24 h and stress-related cell responses (such as apoptosis, oxidative stress, and inflammatory response) were evaluated, along with a broad investigation of graphene oxide impact on specialized hepatic functions. Results show a mild activation of early apoptosis but not oxidative stress or inflammatory response in our cell model. Notably, while graphene oxide clearly impacted phase-I drug-metabolism enzymes (e.g., CYP3A4, CYP2C9) through the inhibition of gene expression and metabolic activity, conversely, no effect was observed for phase-II enzyme GST and phase-III efflux transporter ABCG2. The GO-induced impairment of CYP3A4 occurs concomitantly with the activation of an early acute-phase response, characterized by altered levels of gene expression and protein production of relevant acute-phase proteins (i.e., CRP, Albumin, TFR, TTR). These data suggest that graphene oxide induces an acute phase response, which is in line with recent in vivo findings. In conclusion, upcyte® hepatocytes appear a reliable in vitro model for assessing nanomaterial-induced hepatotoxicity, specifically showing that sub-lethal doses of graphene oxide have a negative impact on the specialized hepatic functions of these cells. The impairment of the cytochrome P450 system, along with the activation of an acute-phase response, may suggest potential detrimental consequences for human health, as altered detoxification from xenobiotics and drugs.

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Section: Discussionmentioning

confidence: 86%

Sub-Lethal Concentrations of Graphene Oxide Trigger Acute-Phase Response and Impairment of Phase-I Xenobiotic Metabolism in Upcyte® Hepatocytes

Romaldini

Spanò

Catalano

et al. 2022

Front. Bioeng. Biotechnol.

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“…To improve mechanical strength, GBNs are ideal nanofillers for polymeric hydrogels, due to their large surface area, flat structure, water dispersibility and biocompatibility, in addition to the intrinsically excellent thermal stability, thermal and electrical conductivity, optical, magnetic, electrochemical, photothermal, photoluminescent, and mechanical properties [6,31,32]. These superior properties make graphene and its derivatives ideal for many biomedical applications, such as anticancer therapy, nanomedicine, drug, gene and protein delivery, antimicrobial agents, biological imaging, molecular biosensors, bioengineering, biotechnology, organic electronics, memory applications, and tissue engineering [2,3,33,34] (Fig. 1).…”

Section: Graphene-based Materialsmentioning

confidence: 99%

“…Nanographene oxide (nGO) is the most popular graphene-based nanofiller due to its good dispersion capacity in water, which is a vital factor for the construction of hydrogels [34]. GO is obtained from graphite powder by oxidative exfoliation using strong oxidants and acids.…”

Section: Graphene-based Materialsmentioning

confidence: 99%

“…Therefore, the main reasons for adding functionalized GO, such as polyethylene glycol (PEG)-nGO, to hydrogels would be their reliable aqueous dispersibility and colloidal stability, enhanced molecular adsorption, increased gene/drug loading capacity, allowing sustained drug release, and improved electrical and thermal conductivity [7,34,36], in addition to their efficacy against various microbes and viruses [8,15]. nGO is often modified with PEG to improve mechanical properties and stability [16,31,34].…”

Section: Graphene-based Materialsmentioning

confidence: 99%

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Graphene-based Nanomaterials: Uses, Environmental Fate, and Human Health Hazards

du Preez,

Halma

2024

Nano Biomedicine and Engineering

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Graphene-based materials (GBMs) possess remarkable physiochemical properties, making them promising for diverse applications in biomedicine, agriculture, food, and industrial applications. Human and environmental exposure to GBMs is increasing at an unprecedented rate, yet there is still a knowledge gap regarding the safety of GBMs. This review summarizes the physiochemical properties of GBMs and critically examines the possible effects of GBMs, both at the level of molecular mechanism and at the level of the organism. While oxidative stress-mediated cell damage has been proposed as a primary cytotoxicity mechanism for GBMs, various in vivo biodistribution and cytotoxicity mechanisms are also highlighted. This review of the literature provides an overview of the cytotoxicity of GBMs, raising concerns about their widespread application with potential hazardous consequences on the environment and in human health.

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“…Graphene oxide (GO) is a biocompatible and attractive nanomaterial for drug delivery. In vitro tests demonstrated that the mRNA expression of PXR and of its target ABCB1 is decreased in intestinal LS180 cells and in PHHs after incubation with GO [272]. PXR protein expression also is downregulated in PHHs, independently of the proteasomal pathway [272].…”

Section: Nanoparticlesmentioning

confidence: 99%

Regulation of CAR and PXR Expression in Health and Disease

Daujat-Chavanieu

Gerbal‐Chaloin

2020

Cells

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Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily that mainly act as ligand-activated transcription factors. Their functions have long been associated with the regulation of drug metabolism and disposition, and it is now well established that they are implicated in physiological and pathological conditions. Considerable efforts have been made to understand the regulation of their activity by their cognate ligand; however, additional regulatory mechanisms, among which the regulation of their expression, modulate their pleiotropic effects. This review summarizes the current knowledge on CAR and PXR expression during development and adult life; tissue distribution; spatial, temporal, and metabolic regulations; as well as in pathological situations, including chronic diseases and cancers. The expression of CAR and PXR is modulated by complex regulatory mechanisms that involve the interplay of transcription factors and also post-transcriptional and epigenetic modifications. Moreover, many environmental stimuli affect CAR and PXR expression through mechanisms that have not been elucidated.

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The effect of graphene oxide on signalling of xenobiotic receptors involved in biotransformation

Cited by 8 publications

References 39 publications

Sub-Lethal Concentrations of Graphene Oxide Trigger Acute-Phase Response and Impairment of Phase-I Xenobiotic Metabolism in Upcyte® Hepatocytes

Sub-Lethal Concentrations of Graphene Oxide Trigger Acute-Phase Response and Impairment of Phase-I Xenobiotic Metabolism in Upcyte® Hepatocytes

Graphene-based Nanomaterials: Uses, Environmental Fate, and Human Health Hazards

Regulation of CAR and PXR Expression in Health and Disease

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