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The liver plays an important role in metabolizing foreign materials, such as drugs. The high accumulation of carbon nanotubes and other hydrophobic nanoparticles in the liver has raised concerns that nanoparticles may interfere with liver metabolic function. We report here that carbon nanotubes enter hepatic cells after intravenous introduction and interact with CYP enzymes, including CYP3A4. Surface chemical modifications alter the carbon nanotubes' interactions with CYP450 enzymes in human liver microsomes. They enhance, inhibit, or have no effect on the enzymatic function of CYP3A4. Using a cheminformatics analysis, certain chemical structures are identified on the surface of the carbon nanotubes that induce an enzyme inhibitory effect or prevent disruption of CYP3A4 enzymes. The high accumulation of multiwalled carbon nanotubes (MWCNTs) in the liver results in their internalization in hepatic cells and perturbations to CYP enzymes, including CYP3A4. Surface chemical modifications on MWCNTs cause enhancement, inhibition, or no effect in CYP3A4 activity. Computational analysis identifies chemical structures on the surface modifications that induce CYP3A4 inhibition or prevent its perturbation.