The role of multidrug transporters in drug availability, metabolism and toxicity.
Multidrug resistance is frequently observed when treating cancer patients with chemotherapeutic agents. A variety of ATP binding cassette (ABC) transporters, localized in the cell membrane, cause this phenomenon by extruding a variety of chemotherapeutic agents from the tumor cells. However, the major physiological role of the multidrug transporters is the protection of our cells and tissues against xenobiotics, and these transporters play a key role in drug availability, metabolism and toxicity. Three major groups of ABC transporters are involved in multidrug resistance: the classical P-glycoprotein MDR1, the multidrug resistance associated proteins (MRP1, MRP2, and probably MRP3, MRP4 and MRP5), and the ABCG2 protein, an ABC half-transporter. All these proteins were shown to catalyze an ATP-dependent active transport of chemically unrelated compounds. MDR1 (P-glycoprotein) and ABCG2 preferentially extrude large hydrophobic, positively charged molecules, while the members of the MRP family can extrude both hydrophobic uncharged molecules and water-soluble anionic compounds. By examining the interactions of the multidrug transporters with pharmacological and toxic agents, a prediction for the cellular and tissue distribution of these compounds can be achieved. Oral bioavailability, entering the blood-brain and blood-CSF barrier, reaching the fetus through the placenta, liver and kidney secretion, cellular entry for affecting intracellular targets, are all questions, which can be addressed by basic in vitro studies on the multidrug resistance proteins. Investigation of the substrate interactions and modulation of multidrug transporters may pave the way for predictive toxicology and pharmacogenomics. Here we show that by using in vitro assay systems it is possible to measure the interactions of multidrug transporters with various drugs and toxic agents. We focus on the characterisation of the MRP1 and MRP3 proteins, their relevance in chemoresistance of cancer and in drug metabolism and toxicity.
Bodó
Adrienn
A
National Medical Center, Institute of Haematology and Immunology, Membrane Research Group of the Hungarian Academy of Sciences, Budapest, Hungary.
Bakos
Eva
E
Szeri
Flóra
F
Váradi
András
A
Sarkadi
Balázs
B
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D001693:Biological Transport, Active / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000009:adverse effects / Q000378:metabolism / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins