Understanding the accumulation of P-glycoprotein substrates within cells: The effect of cholesterol on membrane partitioning

Abstract

The apparent activity of the multidrug transporter P-glycoprotein (P-gp) is enhanced by the presence of cholesterol. Whether this is due to the direct effect of cholesterol on the activity of P-gp, its effect on the local concentration of substrate in the membrane, or its effect on the rate of entry of the drug into the cell, is unknown. In this study, molecular dynamics simulation techniques coupled with potential of mean force calculations have been used to investigate the role of cholesterol in the movement of four P-gp substrates across a POPC bilayer in the presence or absence of 10% cholesterol. The simulations suggest that the presence of cholesterol lowers the free energy associated with entering the middle of the bilayer in a substrate-specific manner. These findings suggest that P-gp substrates may preferentially accumulate in cholesterol-rich regions of the membrane, which may explain its enhanced transport activity.

Shedding light on the puzzle of drug-membrane interactions: Experimental techniques and molecular dynamics simulations

“…They showed that ibuprofen slightly enhanced the order of DMPC lipids, whereas in the presence of 50 mol% cholesterol, the opposite effect was observed [28]. The presence of cholesterol also affects the activity of efflux pumps, such as P-glycoprotein [26]. For instance, Subramanian et al (2016) evaluated the free energy profiles of several drugs within POPC lipid bilayers [26].…”

“…For instance, Subramanian et al (2016) evaluated the free energy profiles of several drugs within POPC lipid bilayers [26]. In the case of doxorubicin and nifedipine, cholesterol reduced their free energy in the centre of the bilayer [26]. Thus, it increased their local concentration in the membrane and, consequently, enhanced P-glycoprotein's ability to expel these drugs [26].…”

“…The presence of cholesterol also affects the activity of efflux pumps, such as P-glycoprotein [26]. For instance, Subramanian et al (2016) evaluated the free energy profiles of several drugs within POPC lipid bilayers [26]. In the case of doxorubicin and nifedipine, cholesterol reduced their free energy in the centre of the bilayer [26].…”

“…In the case of doxorubicin and nifedipine, cholesterol reduced their free energy in the centre of the bilayer [26]. Thus, it increased their local concentration in the membrane and, consequently, enhanced P-glycoprotein's ability to expel these drugs [26]. The effect of cholesterol has also been studied by MD simulations, especially with regards to its effect…”

“…A number of studies are not mentioned in Table 2 since they combined different classes of drugs in the same report. For more information about these studies, please see references [26,100,[118][119][120][121][122][123][124][125][126][127][128]. Some examples will be discussed in detail in the following sections.…”