Perspectives in Pharmacology The Role of ATP Binding Cassette Transporters in Tissue Defense and Organ Regeneration

ATP binding cassette (ABC) transporters are ATP-dependent membrane proteins predominantly expressed in excretory organs, such as the liver, intestine, blood-brain barrier, blood-testes barrier, placenta, and kidney. Here, they play an important role in the absorption, distribution, and excretion of drugs, xenobiotics, and endogenous compounds. In addition, the ABC transporters, P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), are highly expressed in a population of primitive stem cells: the side population (SP). SP cells were originally discovered in bone marrow by their capacity to exclude rhodamine 123 and Hoechst dye 33342; however, extensive research also revealed their presence in other nonhematopoietic tissues. The expression levels of BCRP and P-gp are tightly controlled and may determine the differentiation of SP cells toward other more specialized cell types. Although their exact function in these cells is still not clear, they may protect the cells by pumping out toxicants and harmful products of oxidative stress. Transplantation studies in animals revealed that bone marrow-derived SP cells contribute to organ repopulation and tissue repair after damage, e.g., in liver and heart. The role of SP cells in regeneration of damaged kidney segments is not yet clarified. This review focuses on the role of ABC transporters in tissue defense and regeneration, with specific attention to P-gp and BCRP in organ regeneration and repair. ATP binding cassette (ABC) transporters form one of the largest families of membrane transport proteins expressed in all organisms. This diverse transporter family has been extensively studied, and its members play a vital role in many cellular processes. ABC transporters are responsible for multidrug resistance of cancer cells (Hyde et al., 1990) but may also be capable of transporting several substrates such as metal ions, peptides, amino acids, sugars, and a large number of hydrophobic compounds and metabolites across the plasma membrane as well as intracellular membranes (Dean et al., 2001). The human ABC transporter family consists of 49 members, which are divided into seven subfamilies from A to G based on similarity in gene structure, order of the domains, and sequence homology. Until now, 16 ABC genes have been linked to inherited diseases, such as Tangier disease (ABCA1), Dubin Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6), and cystic fibrosis (ABCC7) (Dean, 2005). Although some ABC transporters have been studied extensively, the functions of many others are still unknown. The development of ABC transporter knockout animals has provided us with some insights into the function and characteristics of ABC transporters (Schinkel et al., 1997; Xia et al., 2007; Glaeser and Fromm, 2008). ABC transporters have an important role in tissue defense through the excretion of toxic compounds and their metabolites (Russel et al., 2002; Szakács et al., 2008). The expression levels of the transporters are tightly regulated, emphasizing their importance in organ protection (Leslie et al., 2005). Moreover, two ABC transporters, the multidrug resistance gene 1 product (MDR1/ABCB1), P-glycoprotein (P-gp), and ABCG2 or breast cancer resistance protein 1 (BCRP), have been implicated in tissue regeneration. Both efflux pumps are highly expressed on side population (SP) cells, a population of primitive bone marrow-derived stem cells with longThis work was supported by the Dutch Kidney Foundation [Grant C02.2012]. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.132225. ABBREVIATIONS: ABC, ATP binding cassette; BCRP, breast cancer resistance protein; P450, cytochrome P-450; HSC, hematopoietic stem cell; MRP, multidrug resistance protein; P-gp, P-glycoprotein; SP, side population; GF120918, elacridar; MDR1, multidrug resistance gene 1. 0022-3565/09/3281-3–9$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 328, No. 1 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 132225/3408067 JPET 328:3–9, 2009 Printed in U.S.A. 3 at A PE T Jornals on M ay 1, 2016 jpet.asjournals.org D ow nladed from term repopulating capacities. A loss of expression leads to cell differentiation, indicating that P-gp and BCRP might determine stem cell-induced tissue remodeling through their differential expression. SP cells have been implicated in the regeneration of various organs, such as liver (Lagasse et al., 2000), skeletal muscles (Jackson et al., 1999), and heart (Jackson et al., 2001). Several studies addressed their participation in renal regeneration, but others excluded their role (Kale et al., 2003; Poulsom et al., 2003; Duffield and Bonventre, 2005; Huls et al., 2008b). Here, an overview of the role of ABC transporters in tissue defense and organ regeneration is given, with a focus on the role of P-gp and BCRP in these processes. Special attention is given to their potential in regeneration of damaged nephron segments after acute kidney injury. ABC Transporters in Tissue Defense The localization of ABC transporters in organs, with a barrier function, and the broad substrate specificities suggest an important role in tissue defense. The efflux pumps are determinants for the absorption, distribution, and excretion of drugs, xenobiotics, and their metabolites (Fig. 1). Entrance in the systemic circulation is prevented by the apical expression of ABC transporters in the intestine (Mao and Unadkat, 2005), like P-gp and BCRP, and the action of these transporters leads to a decreased drug concentration in the liver. The liver is the major site of xenobiotic metabolism in the body, in which enzymes, such as cytochrome P-450 (P450) family members, catalyze the oxidative metabolism of many drugs, eventually affecting both drug efficacy and drug toxicity (Schuetz et al., 1996). P-gp is able to mediate cellular efflux of P450 modulators, like rifampicin. Rifampicin induces CYP3A activity in a dose-dependent manner, thus a lower intracellular concentration results in a decreased CYP3A activity (Schuetz et al., 2000; Yasuda et al., 2002). Drug distribution to the brain is hampered by ABC transporters like P-gp, multidrug resistance proteins 1 and 2 (MRP1/2; ABCC1/2), MRP4 (ABCC4), and BCRP in the blood-brain barrier (Kusuhara and Sugiyama, 2001; Begley, 2004; Perriere et al., 2007). Although these transporters protect the central nervous system, effective drug treatment of brain tumors, epilepsy, and several mental disorders is limited (Fellner et al., 2002; Potschka et al., 2002; Löscher and Potschka, 2005; Gerstner and Fine, 2007; Tate and Sisodiya, 2007). The importance of transporters in the blood-brain barrier was emphasized in mdr1a / mice, which died from the neurotoxic action of ivermectin, a known P-gp substrate, after treatment for mite infestation (Schinkel et al., 1995;