Cytochrome P450 (CYP) enzymes are responsible for oxidative metabolisms of a large number of xenobiotics. In this study, we investigated interactions of silver nanoparticles (AgNPs) and silver ions (Ag+) with six CYP isoforms, namely, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, within CYP-specific inhibitor-binding pockets by molecular docking and quantum mechanical (QM) calculations. The docking results revealed that the Ag3 cluster, not Ag+, interacted with key amino acids of CYP2C9, CYP2C19, and CYP2D6 within a distance of about 3 Å. Moreover, the QM analysis confirmed that the amino acid residues of these CYP enzymes strongly interacted with the Ag3 cluster, providing more insight into the mechanism of the potential inhibition of CYP enzyme activities. Interestingly, these results are consistent with previous in vitro data indicating that AgNPs inhibited activities of CYP2C and CYP2D in rat liver microsomes. It is suggested that the Ag3 cluster is a minimal unit of AgNPs for in silico modeling. In summary, we demonstrated that molecular docking, together with QM analysis, is a promising tool to predict AgNP-mediated CYP inhibition. These methods are useful for deeper understanding of reaction mechanisms and could be used for other nanomaterials.

Silver (Ag) is one of the widely used nanomaterials in cosmetics, personal care, and household products. This research aimed to investigate the Ag concentration contained in 20 commercial nanoproducts using a simple and reliable procedure. The exposure and adverse effects of a single topical application of Ag on the skin were also evaluated. Herein, we demonstrated that the technique of wet acid digestion, extraction and detection of Ag with graphite furnace absorption spectrometry were effective for any and all nanoproduct matrices. The Ag morphology was characterized by scanning and transmission electron microscopy equipped with energy-dispersive x-ray spectroscopy. Penetration of Ag was evaluated using a polyethersulfone (PES) membrane through a Franz cell and reconstructed human epidermis (RhE) tissue. A skin irritation test was performed on RhE, an acceptable in vitro model which was in compliance with OECD test guideline 439. The results showed that the initial Ag concentration in the tested nanoproducts ranged between 0.0058 and 94 lg/g. However, particulate Ag was only found in two products, both of a liquid formulation. Silver penetration through a PES membrane (0.12-53 % by weight) was weakly correlated with the initial Ag concentration in each sample, but more so to the product formulation. The liquid products demonstrated the highest percent of average Ag penetration, followed by the semi-solid and solid formulations, respectively. In contrast, neither any Ag diffusion from these products into the RhE tissue nor any irritation or toxicity was detected. This study suggests a screening method to evaluate the Ag level in products and their potential adverse effects on the skin that could be incorporated as a part of risk assessment for nanotechnology products.

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