Changes in Expression of Drug-Metabolizing Enzymes by Single-Walled Carbon Nanotubes in Human Respiratory Tract Cells

Abstract

ABSTRACT:Single-walled carbon nanotubes (SWCNTs) have attracted attention for biomedical and biotechnological applications, such as drug delivery. However, there are concerns about the safety of SWCNTs for use in humans. To investigate the potential use of SWCNTs for targeted drug delivery to the lung, we examined their effect on drug-metabolizing enzymes in primary normal human bronchial epithelial (NHBE) cells from two donors and the lung carcinoma A549 cell line. Exposure of NHBE and A549 cells to SWCNTs dysregulated some of the important drug-metabolizing enzymes expressed in the human respiratory organs. Exposure of NHBE cells to SWCNTs for 24 h had a pronounced effect on expression of CYP1A1 and CYP1B1 mRNAs, which were reduced to less than 1% of control cells. These effects were also observed in A549 cells. Exposure of A549, HepG2 hepatic carcinoma cells, and MCF-7 breast carcinoma cells to tetrachlorodibenzo-p-dioxin induced the expression and enzymatic activity of CYP1A1 and CYP1B1, which were also suppressed by SWCNTs, suggesting that SWCNTs down-regulated both basal and induced CYP1A1 and CYP1B1 activities. Chromatin immunoprecipitation assays revealed that the down-regulatory effect of SWCNTs may be due to inhibition of activated aryl hydrocarbon receptor binding to the enhancer regions of the CYP1A1 and CYP1B1 genes. Down-regulation of CYP1A1 and CYP1B1 genes by SWCNTs may affect the defense mechanisms by reducing procarcinogen bioactivation in the human lung.

Three human cell types respond to multi-walled carbon nanotubes and titanium dioxide nanobelts with cell-specific transcriptomic and proteomic expression patterns

“…In particular, genes that are transcriptional targets of Ahr, including CYP1A1, CYP1B1 and ARNT2, were down-regulated by MWCNT and up-regulated by TiO 2 -NB depending on time point and cell type. Both CYP1A1 and CYP1B1 expression and enzymatic activity were previously found to be repressed in human A549, HepG2 or MCF-7 cells after exposure to SWCNT (Hitoshi et al 2012). The authors found that SWCNT inhibited both basal and dioxin-induced P450 levels likely by preventing binding of activated Ahr to enhancer regions for these genes.…”

Toxicity of single-walled carbon nanotubes

“…Interestingly, changes in the expression of drug-metabolizing enzymes, such as CYP1A1, CYP1B1, CYP2S1, and CYP19A1, were observed in human respiratory tract cells (NHBE and A549) after the treatment of SWNTs (100 μg/ mL, 24 h exposure) (Hitoshi et al 2012). Down-regulation of CYP1A1 and CYP1B1 may be, in part, due to the reduced binding of the aryl hydrocarbon receptor (AhR) to the enhancer region of CYP1A1 and CYP1B1 (Hitoshi et al 2012).…”

“…Down-regulation of CYP1A1 and CYP1B1 may be, in part, due to the reduced binding of the aryl hydrocarbon receptor (AhR) to the enhancer region of CYP1A1 and CYP1B1 (Hitoshi et al 2012). The exact mechanism by which SWNTs affect the AhR-CYP axis remains to be further elucidated.…”

Biomarkers of susceptibility: State of the art and implications for occupational exposure to engineered nanomaterials

“…In fact, several in vitro studies reported the ability of different metal, metal oxide as well as carbon based and polymeric NPs to acutely (after up to 24 h of treatment) or sub-acutely (after up to 48 h of treatment) affect the gene (Alshatwi et al, 2013; Hitoshi et al, 2012; Periasamy et al, 2014) and mRNA expression (Hitoshi et al, 2012; Lammel et al, 2015) as well as the functionality (Christen and Fent, 2012; Fröhlich et al, 2010; Kulthong et al, 2012; Lu et al, 2013; Lamb et al, 2010; Sereemaspun et al, 2008; Warisnoicharoen et al, 2011; Ye et al, 2014) of CYP metabolic enzymes, although with different results maybe in relation to the type and physico-chemical characteristics of the NPs investigated. Moreover, induction or inhibition of CYP450 gene (Balasubramanian et al, 2010; Ji et al, 2009), mRNA (Cui et al, 2010; Sun et al, 2012) and protein expression (Coccini et al, 2013), as well as alterations in its metabolic functionality (Cho et al, 2010; Kulthong et al, 2012) were also reported in in vivo studies under various conditions of exposure involving a series of different NPs (Table 1).…”