Multidrug Resistance Protein 1, or MRP1, is a protein found within human cells. It functions as a pump, actively moving various substances from inside to outside cells. This action is fundamental to many biological processes, maintaining cellular balance and protecting the body.
Understanding MRP1: The Cellular Guardian
MRP1 is a large protein, approximately 190 kilodaltons and composed of 1531 amino acids. It is situated within the cell’s plasma membrane and also found in internal cellular compartments like mitochondria, the endoplasmic reticulum, and endocytic vesicles. This protein belongs to the ATP-binding cassette (ABC) superfamily of transporters, specifically the ABCC subfamily. Its structure includes five distinct domains: three membrane-spanning domains (MSD0, MSD1, MSD2) that cross the cell membrane 17 times, and two nucleotide-binding domains (NBD1, NBD2) located inside the cell.
MRP1 operates by binding to specific molecules and actively expelling them from the cell. This process requires energy, which MRP1 obtains by breaking down adenosine triphosphate (ATP). The two nucleotide-binding domains form a “sandwich” dimer, creating ATP-binding sites where energy is harnessed. This energy-driven conformational change allows MRP1 to capture substances from the cell’s interior and release them outside.
MRP1’s Essential Role in Detoxification and Cellular Protection
MRP1 removes various harmful substances, toxins, and metabolic waste products from cells. This includes environmental toxins and compounds generated during normal bodily processes. For instance, it transports metalloids like sodium arsenite and potassium antimonite, and toxins such as aflatoxin B1.
MRP1 also manages oxidative stress by transporting oxidized glutathione (GSSG), which helps maintain the cell’s internal environment. It moves inflammatory mediators like cysteinyl leukotriene C4 out of cells, influencing the body’s inflammatory responses. Its ability to transport a wide range of organic anions, including glucuronide and glutathione conjugates, vitamins, and folic acids, impacts cellular health and tissue integrity.
This detoxification activity is relevant in organs frequently exposed to external or internally generated compounds, such as the liver, kidneys, and intestines. By continuously pumping out unwanted molecules, MRP1 helps prevent their accumulation to harmful levels, supporting the proper function and survival of cells throughout the body.
MRP1 and the Challenge of Drug Resistance
While MRP1’s role in cellular detoxification is beneficial, its activity can pose a challenge in medical treatments, particularly cancer chemotherapy. This protein actively pumps therapeutic drugs from cells, reducing their concentration inside target cells and diminishing effectiveness. This contributes to multidrug resistance (MDR), where cells become resistant to various chemically unrelated drugs.
In cancer, tumor cells can overexpress MRP1, producing higher amounts of this protein than normal cells. This overexpression allows cancer cells to efficiently expel anti-cancer drugs, such as anthracyclines (doxorubicin, daunorubicin), vinca alkaloids (vincristine), epipodophyllotoxins (etoposide), methotrexate, and paclitaxel. As a result, drugs cannot reach sufficient concentrations inside cancer cells to kill them, leading to treatment failure.
MRP1-mediated drug resistance impacts treatment outcomes, contributing to reduced response and lower survival rates in patients with various cancers, including lung, breast, prostate, and neuroblastoma. Research continues into strategies to overcome MRP1’s efflux activity, such as developing specific inhibitors (e.g., MK-571, Reversan) or exploring gene silencing techniques to reduce MRP1 expression in cancer cells. Counteracting MRP1’s action in cancer cells remains a focus in developing more effective cancer therapies.