Perturbation of the lipid phase of a membrane is not involved in the modulation of MRP1 transport activity by flavonoids

Abstract

The expression of transmembrane transporter multidrug resistance-associated protein 1 (MRP1) confers the multidrug-resistant phenotype (MDR) on cancer cells. Since the activity of the other MDR transporter, P-glycoprotein, is sensitive to membrane perturbation, we aimed to check whether the changes in lipid bilayer properties induced by flavones (apigenin, acacetin) and flavonols (morin, myricetin) were related to their MRP1 inhibitory activity. All the flavonoids inhibited the efflux of MRP1 fluorescent substrate from human erythrocytes and breast cancer cells. Morin was also found to stimulate the ATPase activity of erythrocyte ghosts. All flavonoids intercalated into phosphatidylcholine bilayers as judged by differential scanning calorimetry and fluorescence spectroscopy with the use of two carbocyanine dyes. The model of an intramembrane localization for flavones and flavonols was proposed. No clear relationship was found between the membrane-perturbing activity of flavonoids and their potency to inhibit MRP1. We concluded that mechanisms other than perturbation of the lipid phase of membranes were responsible for inhibition of MRP1 by the flavonoids.

Degradation of the tricyclic antipsychotic drug chlorpromazine under environmental conditions, identification of its main aquatic biotic and abiotic transformation products by LC–MSn and their effects on environmental bacteria

“…However, it must be considered that sodium acetate was already degraded to more than 50% after two days in these tests. By contrast, the bactericide properties of CPR are more of bacteriostatic origin [23], which might take some time before revealing an effect on bacteria. Additionally, one test bottle in the MRT showed a strong decrease in oxygen consumption, which can be explained by toxic effects through CPR or its photoproducts 335 m/z.…”

“…Whereas some toxic effects are exerted by CPR itself, for instance the ability to promote bilayer condensation [57] or binding to MDR-1 transport channels [23], phototoxicity and photoallergy due to photoproducts of CPR have been reported several times in the literature. The radical cation of CPR seems to play a crucial role in toxicity, since cleavage of the chlorine atom forms a very reactive intermediate, which can bind easily to many cell compounds [38].…”

“…CPR is also discussed as reservedrug against malaria and tuberculosis in developing countries [22]. Whereas some of its antibiotic properties are conducted directly by CPR itself through strong inhibition of P-glycoprotein-mediated transport [23], other studies show that activation of CPR by light exposure has special bactericide effects [20]. It was also this mechanism that made CPR famous for side effects such as photoallergy and phototoxicity during its early years since introduction.…”

The interaction of PVP complexes of gossypol and its derivatives with an artificial membrane lipid matrix

“…To confirm this, we relied mainly on DSC. As lipid systems, multilamellar DMPC and DPPC dispersions were selected, and their thermodynamic properties were thoroughly studied [17,18].…”

A new synthetic approach to phenothiazine-2-amines

“…1 Thus, inhibitors of multidrug resistance, 2 inhibitors of mitotic kinesin Eg5 and trigger apoptosis, 3 potential antimicrobial agents, [4][5][6] antitumor agents, 7 antitubercular compounds, 8 potential chemotherapeutic agents, 9 and antioxidants 10 have been reported.…”