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<p>Zinc oxide (ZnO) nanoparticles are widely applied in biomedical and industrial fields, yet their interactions on drug-metabolizing enzymes remain poorly understood. In this study, ZnO nanorods and nanodisks were synthesized via chemical precipitation and sol-gel methods, respectively, and characterized using FE-SEM, EDX, UV-Vis, FTIR, DLS and ELS. The effects of these nanoparticles on the activity and gene expression of major human cytochrome P450 (CYP) enzymes were systematically evaluated using recombinant enzyme assays and HepG2 cell model, respectively. ZnO nanoparticles induced isoform-specific inhibition of CYP activity, with CYP2C9 being the most susceptible, followed by CYP3A4, CYP2D6, and CYP2C19. The inhibitory potency was dependent on nanoparticle shape, with ZnO nanodisks exhibiting stronger effects than nanorods, as evidenced by consistently lower IC₅₀ and K<sub>i</sub> values across all isoforms (nanodisks: IC₅₀ = 14.04–52.21&#xa0;µg/mL; K<sub>i</sub> = 8.30–25.25&#xa0;µg/mL; nanorods: IC₅₀ = 28.01–89.82&#xa0;µg/mL; K<sub>i</sub> = 9.44–74.07&#xa0;µg/mL). In addition, ZnO exposure upregulated CYP2C9 and CYP3A4 mRNA expression, with a statistically significant increase observed for CYP3A4 following treatment with ZnO nanorods (<i>p</i> &lt; 0.05). Collectively, our findings demonstrate that ZnO nanoparticles altered CYP activity and gene expression in an isoform-specific and shape-dependent manner involving direct enzymatic inhibition and indirect transcriptional regulation, with potential implications for hepatic drug metabolism and nano-drug interaction. This highlights the need to account for potential nanoparticle–drug interactions in the safe and rational design of ZnO-based nanomaterials for biomedical and pharmaceutical applications.</p>

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Impact of ZnO Nanostructure Geometry on the Regulation and Function of Human Cytochrome P450 Enzymes

  • 期刊论文

  • 发表日期：

    2026年7月23日

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  • Ce Lynn Chong,
  • Chee Mun Fang,
  • Swee Yong Pung,
  • Chin Eng Ong,
  • Yuh Fen Pung,
  • Yan Pan

摘要

Zinc oxide (ZnO) nanoparticles are widely applied in biomedical and industrial fields, yet their interactions on drug-metabolizing enzymes remain poorly understood. In this study, ZnO nanorods and nanodisks were synthesized via chemical precipitation and sol-gel methods, respectively, and characterized using FE-SEM, EDX, UV-Vis, FTIR, DLS and ELS. The effects of these nanoparticles on the activity and gene expression of major human cytochrome P450 (CYP) enzymes were systematically evaluated using recombinant enzyme assays and HepG2 cell model, respectively. ZnO nanoparticles induced isoform-specific inhibition of CYP activity, with CYP2C9 being the most susceptible, followed by CYP3A4, CYP2D6, and CYP2C19. The inhibitory potency was dependent on nanoparticle shape, with ZnO nanodisks exhibiting stronger effects than nanorods, as evidenced by consistently lower IC₅₀ and Ki values across all isoforms (nanodisks: IC₅₀ = 14.04–52.21 µg/mL; Ki = 8.30–25.25 µg/mL; nanorods: IC₅₀ = 28.01–89.82 µg/mL; Ki = 9.44–74.07 µg/mL). In addition, ZnO exposure upregulated CYP2C9 and CYP3A4 mRNA expression, with a statistically significant increase observed for CYP3A4 following treatment with ZnO nanorods (p < 0.05). Collectively, our findings demonstrate that ZnO nanoparticles altered CYP activity and gene expression in an isoform-specific and shape-dependent manner involving direct enzymatic inhibition and indirect transcriptional regulation, with potential implications for hepatic drug metabolism and nano-drug interaction. This highlights the need to account for potential nanoparticle–drug interactions in the safe and rational design of ZnO-based nanomaterials for biomedical and pharmaceutical applications.