ABCDrug Transporters and Their Impact on Drug Disposition/Drug Sensitivity and Resistance

Abstract

The “ATP‐binding cassette” superfamily of proteins comprises 49 members, each possessing evolutionarily conserved sequence motifs that lie in the proteins nucleotide (ATP) binding domain. Each member is further classified into seven subclasses (A–G). Most ABC proteins function as membrane‐bound efflux pumps, transporting various small‐molecule substrates from the cytoplasm to the extracellular space; however, there are some exceptions (ABCE and ABCF). A vast array of drugs used in the treatment of diseases such as cancer, HIV, and epilepsy are known substrates of one or more ABC transport pumps. Consequently, the impact of the ABC transport pumps on drug efficacy and resistance has been widely assessed and is explored in this chapter from various perspectives. A focus on cancer drug resistance and the influence of the key ABC proteins ABCB1, ABCC1, ABCC2, and ABCG2 is presented along with a look into the contributions of these proteins to adverse reactions. The chapter concludes with a look into the genetics of the ABC transport pumps, including the genetic regulation of these proteins. The influence of single nucleotide polymorphisms identified within the ABC genes on the efficacy of drugs is discussed in depth. Lastly, the chapter assesses disease states that arise from abnormalities in ABC genes.

The translational expression of ABCA2 and ABCA3 is a strong prognostic biomarker for multidrug resistance in pediatric acute lymphoblastic leukemia

“…Previous clinical studies have shown that estramustine is sequestered and effluxed by ABCA2 in resistant ovarian carcinoma 13,37. Docking analysis performed on a predicted model of ABCA2 suggested that ABCA2 is able to bind estramustine (docking grid energy equal to −42.395 kcal/mol) (data not shown).…”

“…Previous clinical studies have shown that estramustine is sequestered and effluxed by ABCA2 in resistant ovarian carcinoma. 13 , 37 Docking analysis performed on a predicted model of ABCA2 suggested that ABCA2 is able to bind estramustine (docking grid energy equal to −42.395 kcal/mol) (data not shown). The overlap between the ABCA2 and ABCA3 models obtained by Phyre2 outlined the presence of similar domains (ie, transmembrane helixes and nucleotide-binding domains) ( Figure 3A ).…”