title: Changes in expression of drug-metabolizing enzymes by single-walled carbon nanotubes in human respiratory tract cells.
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.
authors.affiliation: Pharmaceutics, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hitoshi
authors.forename: Miki
authors.initials: M
authors.lastname: Katoh
authors.forename: Tomoko
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ando
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nadai
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D037742:Nanotubes, Carbon / Q000737:chemistry*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D012137:Respiratory System / Q000378:metabolism*
chemical_list: D037742:Nanotubes, Carbon; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D001189:Aryl Hydrocarbon Hydroxylases; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1