The ATP-binding cassette sub-family G member 2, widely known as ABCG2, is a protein transporter embedded in the membranes of cells throughout the human body. This protein functions as a cellular gatekeeper, actively controlling the movement of numerous substances across the cell boundary. Its primary role is as an efflux pump, meaning it pushes compounds out of the cell to provide defense against potentially harmful materials. ABCG2 handles a broad range of compounds, from natural metabolites to therapeutic drugs, establishing its importance in maintaining cellular function and overall health.
The Mechanism of Cellular Defense
The core biological function of ABCG2 is xenobiotic defense, protecting cells from the internal accumulation of foreign or toxic compounds. As a member of the ATP-binding cassette (ABC) transporter superfamily, ABCG2 utilizes energy derived from the breakdown of adenosine triphosphate (ATP) to perform its transport activity. The protein couples the energy released from ATP hydrolysis to the movement of substances.
This energy conversion drives conformational changes within the transporter. The protein transforms from an inward-facing state, where it binds a substrate from inside the cell, to an outward-facing state, where the substrate is released outside the cell. This continuous, active, one-way efflux prevents the buildup of compounds. This mechanism allows the cell to maintain a low internal concentration of a wide variety of structurally diverse compounds.
Influence on Drug Absorption and Distribution
ABCG2’s strategic location in various tissues dictates its significant influence on the body’s handling of medications, a process known as pharmacokinetics.
In the intestinal lining, ABCG2 is highly expressed on the apical membranes of epithelial cells facing the gut lumen. Here, it acts as a barrier, pumping orally administered drugs back into the intestine. This action limits their absorption into the bloodstream and reduces overall drug bioavailability.
The transporter is also present in organs responsible for elimination, such as the liver and kidneys. In the liver, ABCG2 actively secretes compounds and drug metabolites into the bile for eventual removal from the body. Similarly, in the kidneys, it contributes to the secretion of substances into the urine, affecting the rate of drug excretion.
ABCG2 also forms part of protective physiological barriers, including the blood-brain barrier and the placenta. At the blood-brain barrier, the transporter actively extrudes drugs from the endothelial cells lining the microvessels, restricting access to the central nervous system. This protective action can pose a challenge for treating neurological conditions. In the placenta, ABCG2 limits the transfer of xenobiotics from the maternal circulation to the fetus.
Impact on Disease Progression and Treatment
ABCG2 activity is clinically relevant in the context of certain diseases, notably cancer and gout.
Cancer and Multidrug Resistance
In oncology, the protein is frequently referred to as Breast Cancer Resistance Protein (BCRP), due to its discovery in resistant cancer cells. Overexpression of ABCG2 in tumor cells is a primary mechanism contributing to multidrug resistance in chemotherapy. The transporter efficiently recognizes and pumps out numerous anti-cancer drugs, such as topotecan and mitoxantrone. This action lowers their effective concentration within the cancer cell and renders the treatment ineffective.
Gout and Uric Acid Transport
In gout, a condition characterized by high levels of uric acid in the blood (hyperuricemia), ABCG2 plays a distinct physiological role. It functions as a high-capacity transporter for uric acid, facilitating its excretion, particularly through the intestine. Dysfunction or reduced activity of ABCG2 impairs the body’s ability to eliminate uric acid. This reduced clearance increases the risk for hyperuricemia and the development of painful gout flares.
Genetic Variability and Drug Interactions
Individual responses to medications are significantly influenced by natural variations, or genetic polymorphisms (SNPs), in the ABCG2 gene. These variations can alter the transporter’s expression or function. A well-studied variant, Q141K (rs2231142), results in a reduced amount of functional ABCG2 protein reaching the cell membrane, leading to decreased transport activity.
This reduced function can cause two opposing clinical outcomes depending on the substrate. For certain drug substrates, the diminished efflux pump activity leads to higher-than-expected drug levels in the bloodstream, increasing the risk of adverse side effects or toxicity. Conversely, for uric acid, the impaired transport activity results in a reduced ability to excrete the metabolite, which is a significant genetic factor predisposing individuals to hyperuricemia and early-onset gout.
Beyond genetics, the activity of ABCG2 can be modulated by external agents, leading to significant drug interactions.
Modulating Agents
Some co-administered substances can act as inhibitors, blocking the function of the ABCG2 transporter. This inhibition increases the systemic exposure of an ABCG2 substrate drug, potentially leading to toxic concentrations. Other agents can act as inducers, increasing the production or activity of ABCG2, which may accelerate the drug’s clearance and reduce its therapeutic effectiveness.