ABCG2

ABCG2, as a member of the ATP-binding cassette (ABC) transporter family, is involved in cellular transport mechanisms.  The ABC transporter family is particularly effective in effluxing a wide range of substrates, including drugs and metabolites, across cellular membranes. 

Also known as a breast cancer resistance protein, this protein acts as a xenobiotic transporter and is implicated in multi-drug resistance. It likely acts as a cellular defense mechanism against some toxic substances. 

High levels of expression of this protein have also been noted in the placenta, indicating a possible involvement in placental function.

ABCG2 is implicated in influencing drug pharmacokinetics, contributing to multidrug resistance in cancer, and playing a role in the pathophysiology of certain diseases.

What is ABCG2?  [1.]

The ABCG2 gene is a member of the ATP-binding cassette superfamily, and a member of the White subfamily.  ABCG2, also known as the Breast Cancer Resistance Protein (BCRP), is a protein responsible for the transport of various molecules across cellular membranes, influencing numerous physiological and pathological processes.

The human breast cancer resistance protein (BCRP) was so named because it was initially isolated from a multidrug-resistant breast cancer cell line: BCRP was found to confer resistance to chemotherapeutic drugs like mitoxantrone and topotecan. 

Since its discovery in 1998, BCRP has been found to transport not only therapeutic agents but also endogenous compounds such as estrogens, and uric acid. Moreover, numerous inhibitors of BCRP have been identified over the years.  [3.]

ABCG2 is predominantly expressed in the placenta, liver, intestine, the blood-brain barrier and in breast tissue.  It is also expressed in other tissues.  Its function has been implicated in normal physiological function as well as in the pathophysiology of certain diseases, particularly some cancers.  [4.]

Its presence in normal tissue suggests its vital role in protecting the body from toxins and in the pharmacokinetics of drugs.  [4.] 

In the placenta, it is believed to protect the fetus from exposure to harmful substances. In the liver and intestine, it contributes to the detoxification process and the excretion of drugs and metabolites. At the blood-brain barrier, ABCG2 helps maintain the brain's environment by restricting the entry of potentially harmful compounds.  [4.]

The health benefits provided by ABCG2 in protecting healthy human cells from toxins may be the same mechanism by which it provides multidrug resistance: by blocking the drug from reaching its intended target tissue.  [2., 4.]   

 The gene is regulated by a range of factors, including hormones, dietary components, and endogenous substances. This regulation plays a vital role in modulating the absorption, distribution, metabolism, and excretion of drugs, contributing to individual variations in drug response.

The gene for the ABCG2 protein may contain alterations or mutations that cause loss of function of the enzymes and can confer increased risk of disease in affected humans.  Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Functions of ABCG2

The ABCG2 protein, also known as the human Breast Cancer Resistance Protein, is an ATP-binding cassette efflux transporter responsible for mediating the cellular extrusion of various substrates.  Many substrates have been identified including chemotherapeutic agents and endogenous compounds, indicating its role in maintaining cellular health, physiological homeostasis, and drug resistance.  [2., 3.]

ABCG2 and Cellular Health [2.]

The ABCG2 protein, also known as the breast cancer resistance protein (BCRP), serves as a crucial defense mechanism for cells against toxins and xenobiotics.  

It functions as an efflux transporter, actively pumping out various harmful substances from cells, thereby protecting them from potential damage. Moreover, ABCG2 plays a significant role in transporting essential vitamins and nutrients, ensuring their distribution throughout the body.

This dual functionality underscores the pivotal role of ABCG2 in cellular homeostasis and overall health maintenance, emphasizing its importance as a key player in cellular detoxification and nutrient transport processes.

ABCG2 and Multi Drug Resistance [2., 4.]

Multidrug resistance (MDR) represents a formidable challenge across infectious disease therapy and cancer chemotherapy, characterized by cells or organisms resisting the cytotoxic effects of diverse chemical structures. 

In humans, MDR is primarily associated with cancer chemotherapy failure.  It  involves ATP binding cassette (ABC) proteins, notably ABCG2 (breast cancer resistance protein), among others like ABCB1 and ABCC1. 

ABCG2, a prominent member of the ABC transporter family, mediates the efflux of various anticancer drugs and physiological compounds, playing a crucial role in drug resistance and metabolic pathways. 

Moreover, ABCG2's involvement extends to transporting sulfate and glucuronide conjugates, as well as potentially influencing photodynamic therapy resistance and contributing to cerebral amyloid angiopathy in Alzheimer’s disease patients through Aβ peptide transport at the blood-brain barrier.

ABCG2 and Cancer [4.]

In cancer, the overexpression of ABCG2 is often associated with the development of resistance to chemotherapy drugs. This is particularly evident in breast cancer, leukemia, and certain types of lung cancer, where ABCG2 acts as an efflux pump, removing chemotherapeutic agents from cancer cells and thus reducing their effectiveness.

ABCG2 and Cardiovascular Diseases

In cardiovascular diseases, ABCG2's role is emerging in the context of cholesterol regulation and atherosclerosis. Studies suggest that ABCG2 can influence cholesterol efflux from cells, a process crucial in preventing plaque formation in blood vessels. Additionally, variations in the ABCG2 gene has been shown to function as a statin efflux pump. [5.] 

ABCG2 and Gout

The connection between ABCG2 and gout is well-established, with certain variants of the ABCG2 gene significantly increasing the risk of this condition. ABCG2 is involved in urate transport; mutations in this gene can lead to decreased excretion of uric acid, contributing to the development of hyperuricemia and gout. [3.]

Lab Testing for ABCG2

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test. This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results. Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Genetic Testing in Cancer

In the context of cancer, where ABCG2 is implicated in drug resistance, testing for a panel of drug resistance-related genes can provide a more detailed picture of a tumor’s characteristics and potential responsiveness to chemotherapy.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

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