Nanoparticles have become ubiquitous in today’s society with a current estimate suggesting over 800 nanoparticle containing consumer goods. More recently they have been extensively explored as drug delivery vehicles. Buckminster fullerene (C60) nanoparticles have attracted attention as a drug delivery method due to their size, geometry, and surface characteristics. There is a dearth of studies of the effect of nanoparticles, such as C60, on Cytochrome P450s (P450s) which are responsible for 75% of metabolism of pharmaceuticals on the market. P450s are a large family of heme containing proteins found primarily in the liver where they are associated with the smooth endoplasmic reticulum. In order to use C60s safely (e.g., as a drug delivery vehicles) it is important to understand its effects on biological systems, especially that of the liver which is crucial to xenobiotic metabolism. Here we show molecular modeling studies of C60 binding to P450 externally and within the active site demonstrating favorable interactions, which might implicate a modulation of P450 metabolism in the presence of C60. The molecular modeling hypothesis was further confirmed by <i>in vitro</i> binding observed in Surface Plasmon Resonance of C60 to CYP2C9. Metabolism studies reveal a dose dependent inhibition of two P450 isoforms, CYP2C9 and CYP2D6 which play important roles in xenobiotic metabolism at physiologically relevant concentrations of C60. In contrast, we show that Single Walled Carbon Nanotubes, which have the same carbon chemistry as C60, show no inhibition of P450s, but rather cause activation of metabolism at high doses. Lastly, Nuclear Magnetic Resonance studies show a possible effect on substrate entry into the active site in the presence of C60. Thus we show our molecular modeling successfully predicts C60 interaction with P450s, and that this interaction causes changes in P450 mediated metabolism. These experiments will help elucidate the effects of C60 on P450 mediated metabolism and determine potential undesired interactions at physiologically relevant concentrations.<br/><br/>We acknowledge support from the National Science Foundation (Cooperative Agreement 1003907) and NIH (GM081348).

Buckminster fullerene effect on cytochrome P450 mediated metabolism

249th National Meeting (2015)

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