The ABCG2/BCRP transporter and its variants – from structure to pathology

Abstract

The ABCG2 protein has a key role in the transport of a wide range of structurally dissimilar endo-and xenobiotics in the human body, especially in the tissue barriers and the metabolizing or secreting organs. The human ABCG2 gene harbors a high number of polymorphisms and mutations, which may significantly modulate its expression and function. Recent high-resolution structural data, complemented with molecular dynamic simulations, may significantly help to understand intramolecular movements and substrate handling, as well as the effects of mutations on the membrane transporter function of ABCG2. As reviewed here, structural alterations may result not only in direct alterations in drug binding and transporter activity, but also in improper folding or problems in the carefully regulated process of trafficking, including vesicular transport, endocytosis, recycling, and degradation. Here, we also review the clinical importance of altered ABCG2 expression and function in general drug metabolism, cancer multidrug resistance, and impaired uric acid excretion, leading to gout.

Bisphenol A Inhibits the Transporter Function of the Blood-Brain Barrier by Directly Interacting with the ABC Transporter Breast Cancer Resistance Protein (BCRP)

“…One group of BBB transporters is comprised of the ATP-binding cassette (ABC) transporters [ 7 , 8 , 9 ], including the breast cancer resistance protein (BCRP; coded by the gene ABCG2 ). The BCRP is an efflux transporter that can actively export a range of endogenous and exogenous substrates from the brain to the blood, thereby facilitating the maintenance of brain homeostasis, as well as protecting the brain against xenobiotics [ 7 , 8 , 9 , 10 ]. The BCRP transporter is not specific for the BBB but is highly expressed in barrier cells in, e.g., the colon, small intestine, placenta, and liver [ 11 , 12 ].…”

A pharmacogenetics study of platinum-based chemotherapy in lung cancer: ABCG2 polymorphism and its genetic interaction with SLC31A1 are associated with response and survival

“…We selected thirteen tagging and functional SNPs of ABCG2 , including eleven intronic (rs6857600, rs3109823, rs2725252, rs17731538, rs2231138, rs11931123, rs1871744, rs2231146, rs12505410, rs4148157 and rs2231164) and two nonsynonymous (rs2231137, Val12Met; rs2231142, Gln141Lys) variations, among which the nonsynonymous rs2231142 reportedly leads to reduced ABCG2 protein level and efflux transporter functionality 26 . In order to address the consistency of genetic association for the multi-center NSCLC cohorts, we genotyped all of these polymorphisms in both the discovery panel A and the replication panel B.…”

Ganciclovir and Its Hemocompatible More Lipophilic Derivative Can Enhance the Apoptotic Effects of Methotrexate by Inhibiting Breast Cancer Resistance Protein (BCRP)

“…It was also demonstrated in the present study that both GCV and its more lipophilic derivative 1 were interacting with BCRP, since a selective BCRP-selective inhibitor, FMC, was able to increase the amount of these compounds in the MCF-7 cells, when incubating FMC together with these compounds ( Figure 3 B). However, in this study, the conclusions were based only on the competitive cellular uptake studies, and thus more sophisticated methods, e.g., computational modeling, are needed to clarify the exact interactions between the compounds and BCRP [ 28 , 29 , 30 ]. Curiously, interactions of GCV and other anticancer nucleosides with BCRP have been demonstrated also in other studies [ 31 , 32 ], which supports our conclusions.…”