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

Author(s)

dos Santos, Kevin F. ; Materon, Elsa M. ; Oliveira Jr, Osvaldo N.

• Document type: Journal article
• Source: COLLOIDS AND SURFACES B-BIOINTERFACES; v. 220, p. 9-pg., 2022-12-01.

Abstract

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-alpha-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. (AU)

• FAPESP's process: 16/00991-5 - Study of Detoxification Enzymes Interaction with chemotherapeutic drugs and its relationship with chemoresistance
• Grantee: Elsa María Materón Vásques
• Support Opportunities: Scholarships in Brazil - Post-Doctoral