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Expression, Detergent Solubilization, and Purification of a Membrane Transporter, the MexB Multidrug Resistance Protein
Published on: December 3, 2010
A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1
1Mayo Clinic College of Medicine, Scottsdale, AZ 85259, USA. xbchang@mayo.edu
Abstract:
Over a million new cases of cancers are diagnosed each year in the United States and over half of these patients die from these devastating diseases. Thus, cancers cause a major public health problem in the United States and worldwide. Chemotherapy remains the principal mode to treat many metastatic cancers. However, occurrence of cellular multidrug resistance (MDR) prevents efficient killing of cancer cells, leading to chemotherapeutic treatment failure. Numerous mechanisms of MDR exist in cancer cells, such as intrinsic or acquired MDR. Overexpression of ATP-binding cassette (ABC) drug transporters, such as P-glycoprotein (P-gp or ABCB1), breast cancer resistance protein (BCRP or ABCG2) and/or multidrug resistance-associated protein (MRP1 or ABCC1), confers an acquired MDR due to their capabilities of transporting a broad range of chemically diverse anticancer drugs. In addition to their roles in MDR, there is substantial evidence suggesting that these drug transporters have functions in tissue defense. Basically, these drug transporters are expressed in tissues important for absorption, such as in lung and gut, and for metabolism and elimination, such as in liver and kidney. In addition, these drug transporters play an important role in maintaining the barrier function of many tissues including blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier. Thus, these ATP-dependent drug transporters play an important role in the absorption, disposition and elimination of the structurally diverse array of the endobiotics and xenobiotics. In this review, the molecular mechanism of ATP-dependent solute transport by MRP1 will be addressed.
Insights
Multidrug resistance (MDR) in cancer hinders chemotherapy. ATP-binding cassette (ABC) transporters like MRP1 contribute to MDR and play vital roles in tissue defense and drug disposition.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cancer is a major public health issue, with chemotherapy being a primary treatment for metastatic disease.
- Cellular multidrug resistance (MDR) significantly limits the efficacy of chemotherapy, leading to treatment failure.
- ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 1 (MRP1), are key mediators of acquired MDR.
Purpose of the Study:
- To review the molecular mechanisms of ATP-dependent solute transport by MRP1.
- To highlight the dual role of ABC transporters in both cancer MDR and physiological tissue defense.
- To discuss the involvement of these transporters in the absorption, distribution, metabolism, and excretion (ADME) of various compounds.
Main Methods:
- Literature review focusing on the molecular mechanisms of MRP1.
- Analysis of studies investigating ABC transporter function in cancer cells and healthy tissues.
- Synthesis of information regarding the structure and function of MRP1 in solute transport.
Main Results:
- MRP1, along with other ABC transporters, actively effluxes a wide range of anticancer drugs, contributing to MDR.
- These transporters are crucial for protecting tissues by eliminating xenobiotics and endobiotics.
- MRP1 is expressed in barrier tissues, influencing the disposition of substances across biological membranes.
Conclusions:
- Understanding the molecular transport mechanism of MRP1 is critical for overcoming chemotherapy resistance.
- Targeting ABC transporters may offer strategies to enhance cancer treatment efficacy.
- The physiological roles of MRP1 in tissue defense and ADME are intrinsically linked to its role in MDR.
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