Mammalian ABC Transporters in Health and Disease

Abstract

f Abstract The ATP-binding cassette (ABC) transporters are a family of large proteins in membranes and are able to transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. The available outline of the human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease. Major physiological functions of ABC transporters include the transport of lipids, bile salts, toxic compounds, and peptides for antigen presentation or other purposes. We review the functions of mammalian ABC transporters, emphasizing biochemical mechanisms and genetic defects. Our overview illustrates the importance of ABC transporters in human physiology, toxicology, pharmacology, and disease. We focus on three topics: (a) ABC transporters transporting drugs (xenotoxins) and drug conjugates. (b) Mammalian secretory epithelia using ABC transporters to excrete a large number of substances, sometimes against a steep concentration gradient. Several inborn errors in liver metabolism are due to mutations in one of the genes for these pumps; these are discussed. (c) A rapidly increasing number of ABC transporters are found to play a role in lipid transport. Defects in each of these transporters are involved in human inborn or acquired diseases.

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

“…Professional lipid ABC transporters, such as the cholesterol and phospholipid transporter ABCA1, the long-chain PC and cholesterol transporter ABCB4 (MDR3), the bile salt transporter ABCB11 (BSEP/S-P-gp), or the major sterol transporters ABCG5/G8 (working as an obligate heterodimer), have indeed been shown to be regulated by lipid-sensing NRs (Beyea et al, 2007;Jonker et al, 2009;Schmitz & Langmann, 2005;Tarling et al, 2013;van Meer et al, 2008). Interestingly, to date, several NRs also involved in the recognition of lipid ligands have been shown to affect the gene expression of human ABCB1 and ABCG2, the transport functions of which are mainly involved in causing multidrug resistance (Borst & Elferink, 2002;Jonker et al, 2009;Klaassen & Aleksunes, 2010;Natarajan, Xie, Baer, & Ross, 2012;Sarkadi et al, 2006;Scotto, 2003). Therefore, via binding to and activating their cognate NRs, lipid molecules might also be directly involved in the transcriptional regulation of both ABCB1 and ABCG2.…”

MDR1 in immunity: friend or foe?

“…1,2 This efflux pump can exclude several substances such as medical drugs from cells. Consequently, its role has been largely investigated in cancer cells owing to its contribution in chemotherapy resistances.…”

“…8 At the protein level (Figure 1), MDR1 is formed by a single 170 kDa monomer of 12 transmembrane domains (TMs), glycosylated on its first extracellular loop (between TM1 and 2). 1,2 Two distinct cytoplasmic ATP binding sites, respectively located on the loop between the TMs 6 and 7 and after the TM 12, work alternatively and cooperatively to efflux the substrate. 9

10.1080/2162402X.2018.1499388-F0001Figure 1.Protein structure and conformation of MDR1.MDR1 is composed of 12 transmembrane domains (TMs) and two cytoplasmic ATP binding domains located on the loop between the TMs 6 and 7 and the loop after the TM 12.

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“…1 We find some endogenous compounds like amyloid-β, steroids and platelet-activating factor (PAF) 5–7,14 but mainly a very large number of therapeutic drugs (Table 1). 15 However, two other important ABC transporters, Breast Cancer Resistance Protein 1 (BCRP-1) 16 and Multidrug Resistance Protein 1 (MRP-1), 17 have also been implicated in chemotherapeutic resistance with a partially shared substrate specificity with MDR1 (Table 1).…”

Molecular analysis, developmental function and heavy metal-induced expression of ABCC5 in zebrafish

“…Multidrug resistance-associated proteins (MRPs) are members of the subfamily C of ABC transporters, which are able to transport a wide variety of substrates against steep concentration gradients at the cost of ATP hydrolysis (Borst and Elferink, 2002). MRPs recognize natural product drugs, conjugated and unconjugated organic anions as substrates.…”