title: Single-Walled Carbon Nanotubes Inhibit the Cytochrome P450 Enzyme, CYP3A4.
abstract: We report a detailed computational and experimental study of the interaction of single-walled carbon nanotubes (SWCNTs) with the drug-metabolizing cytochrome P450 enzyme, CYP3A4. Dose-dependent inhibition of CYP3A4-mediated conversion of the model compound, testosterone, to its major metabolite, 6β-hydroxy testosterone was noted. Evidence for a direct interaction between SWCNTs and CYP3A4 was also provided. The inhibition of enzyme activity was alleviated when SWCNTs were pre-coated with bovine serum albumin. Furthermore, covalent functionalization of SWCNTs with polyethylene glycol (PEG) chains mitigated the inhibition of CYP3A4 enzymatic activity. Molecular dynamics simulations suggested that inhibition of the catalytic activity of CYP3A4 is mainly due to blocking of the exit channel for substrates/products through a complex binding mechanism. This work suggests that SWCNTs could interfere with metabolism of drugs and other xenobiotics and provides a molecular mechanism for this toxicity. Our study also suggests means to reduce this toxicity, eg., by surface modification.
authors.affiliation: Nanosafety &Nanomedicine Laboratory, Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Ramy
authors.initials: R
authors.lastname: El-Sayed
authors.affiliation: Nanosafety &Nanomedicine Laboratory, Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Kunal
authors.initials: K
authors.lastname: Bhattacharya
authors.affiliation: Institute of Quantitative Biology and Medicine, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
authors.forename: Zonglin
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Institute of Quantitative Biology and Medicine, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
authors.forename: Zaixing
authors.initials: Z
authors.lastname: Yang
authors.affiliation: IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598, USA.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Weber
authors.affiliation: Department of Engineering Sciences, Uppsala University, 75121 Uppsala, Sweden.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Engineering Sciences, Uppsala University, 75121 Uppsala, Sweden.
authors.forename: Klaus
authors.initials: K
authors.lastname: Leifer
authors.affiliation: Functional Materials Division, Department of Materials and Nanophysics, KTH-Royal Institute of Technology, 16440 Stockholm, Sweden.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Functional Materials Division, Department of Materials and Nanophysics, KTH-Royal Institute of Technology, 16440 Stockholm, Sweden.
authors.forename: Muhammet S
authors.initials: MS
authors.lastname: Toprak
authors.affiliation: Institute of Quantitative Biology and Medicine, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.|IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598, USA.|Department of Chemistry, Columbia University, New York, New York 10027, USA.
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Nanosafety &Nanomedicine Laboratory, Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden.|Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
mesh_terms: D000818:Animals; D002417:Cattle; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D008658:Inactivation, Metabolic / Q000187:drug effects*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D037742:Nanotubes, Carbon / Q000009:adverse effects / Q000737:chemistry*; D011487:Protein Conformation / Q000187:drug effects; D013739:Testosterone / Q000378:metabolism
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D037742:Nanotubes, Carbon; D013739:Testosterone; D051544:Cytochrome P-450 CYP3A