Influence of cytochrome P450 3A4 and membrane lipid composition on doxorubicin activity

• Published in: Colloids and surfaces, B, Biointerfaces B, Biointerfaces, 2022-12, Vol.220, p.112886-112886, Article 112886
• Main Authors: dos Santos, Kevin F., Materón, Elsa M., Oliveira, Osvaldo N.
• Format: Article
• Language: English
• Subjects: Cytochrome P450 3A4. Doxorubicin. Langmuir monolayers. Membrane models. Drug resistance
• ISSN: 0927-7765; 1873-4367
• DOI: 10.1016/j.colsurfb.2022.112886

Drug resistance is known to depend on the interactions with cell membranes and other molecules such as human cytochromes P450 (CYPs) which are anchored on the endoplasmic reticulum (ER) membrane and involved in the metabolism of anticancer drugs. In this study, we determined the influence from cytochrome P450 3A4 (CYP3A4) on the interaction between the drug doxorubicin (DOX) and Langmuir monolayers mimicking cell membranes. The lipid composition was varied by changing the relative concentrations of cholesterol (Chol), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and L-α-phosphatidylinositol (PI). Three compositions were studied in detail which represented a healthy cell membrane and cancerous cell membranes. DOX induced an expansion in the surface pressure isotherms for all monolayers, with stronger effect for the composition of cancerous cell with a high Chol content, thus confirming the relevance of lipid composition. This effect decreased considerably when CYP3A4 was incorporated with the formation of CYP3A4-DOX complexes, according to results from polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS) measurements. Taken together, these results support the hypothesis of CYP3A4 being involved in drug resistance, which may be exploited to design strategies to enhance chemotherapy efficacy. [Display omitted] •The incorporation of CYP3A4 varied with monolayer composition.•DOX increased the monolayer area and fluidity according to Chol and PI contents.•CYP3A4 attenuated DOX effects on the monolayers.