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

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The Role of ATP Binding Cassette Transporters in Tissue Defense and Organ Regeneration 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. Perspectives in Pharmacology The Role of ATP Binding Cassette Transporters in Tissue Defense and Organ Regeneration Miriam Huls, Frans G. M. Russel, and Rosalinde Masereeuw Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, The Netherlands Downloaded from Received July 22, 2008; accepted September 11, 2008 ABSTRACT ATP binding cassette (ABC) transporters are ATP-dependent tissues. The expression levels of BCRP and P-gp are tightly con- membrane proteins predominantly expressed in excretory organs, trolled and may determine the differentiation of SP cells toward jpet.aspetjournals.org such as the liver, intestine, blood-brain barrier, blood-testes bar- other more specialized cell types. Although their exact function in rier, placenta, and kidney. Here, they play an important role in these cells is still not clear, they may protect the cells by pumping the absorption, distribution, and excretion of drugs, xenobiotics, out toxicants and harmful products of oxidative stress. Transplan- and endogenous compounds. In addition, the ABC transporters, tation studies in animals revealed that bone marrow-derived SP P-glycoprotein (P-gp/ABCB1) and breast cancer resistance cells contribute to organ repopulation and tissue repair after dam- protein (BCRP/ABCG2), are highly expressed in a population of age, e.g., in liver and heart. The role of SP cells in regeneration of primitive stem cells: the side population (SP). SP cells were orig- damaged kidney segments is not yet clarified. This review focuses inally discovered in bone marrow by their capacity to exclude on the role of ABC transporters in tissue defense and regenera- at ASPET Journals on April 2, 2015 rhodamine 123 and Hoechst dye 33342; however, extensive re- tion, with specific attention to P-gp and BCRP in organ regener- search also revealed their presence in other nonhematopoietic ation and repair. ATP binding cassette (ABC) transporters form one of the linked to inherited diseases, such as Tangier disease largest families of membrane transport proteins expressed in (ABCA1), Dubin Johnson syndrome (ABCC2), pseudoxan- all organisms. This diverse transporter family has been ex- thoma elasticum (ABCC6), and cystic fibrosis (ABCC7) tensively studied, and its members play a vital role in many (Dean, 2005). Although some ABC transporters have been cellular processes. ABC transporters are responsible for mul- studied extensively, the functions of many others are still tidrug resistance of cancer cells (Hyde et al., 1990) but may unknown. The development of ABC transporter knockout also be capable of transporting several substrates such as animals has provided us with some insights into the function metal ions, peptides, amino acids, sugars, and a large num- and characteristics of ABC transporters (Schinkel et al., ber of hydrophobic compounds and metabolites across the 1997; Xia et al., 2007; Glaeser and Fromm, 2008). plasma membrane as well as intracellular membranes (Dean ABC transporters have an important role in tissue defense et al., 2001). through the excretion of toxic compounds and their metabo- The human ABC transporter family consists of 49 mem- lites (Russel et al., 2002; Szaka´cs et al., 2008). The expression bers, which are divided into seven subfamilies from A to G levels of the transporters are tightly regulated, emphasizing based on similarity in gene structure, order of the domains, their importance in organ protection (Leslie et al., 2005). and sequence homology. Until now, 16 ABC genes have been Moreover, two ABC transporters, the multidrug resistance gene 1 product (MDR1/ABCB1), P-glycoprotein (P-gp), and This work was supported by the Dutch Kidney Foundation [Grant ABCG2 or breast cancer resistance protein 1 (BCRP), have C02.2012]. been implicated in tissue regeneration. Both efflux pumps Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. are highly expressed on side population (SP) cells, a popula- doi:10.1124/jpet.107.132225. tion of primitive bone marrow-derived stem cells with long- 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. 3 4 Huls et al. term repopulating capacities. A loss of expression leads to intracellular concentration results in a decreased CYP3A cell differentiation, indicating that P-gp and BCRP might activity (Schuetz et al., 2000; Yasuda et al., 2002). determine stem cell-induced tissue remodeling through their Drug distribution to the brain is hampered by ABC trans- differential expression. SP cells have been implicated in the porters like P-gp, multidrug resistance proteins 1 and 2 regeneration of various organs, such as liver (Lagasse et al., (MRP1/2; ABCC1/2), MRP4 (ABCC4), and BCRP in the 2000), skeletal muscles (Jackson et al., 1999), and heart blood-brain barrier (Kusuhara and Sugiyama, 2001; Begley, (Jackson et al., 2001). Several studies addressed their par- 2004; Perriere et al., 2007). Although these transporters pro- ticipation in renal regeneration, but others excluded their tect the central nervous system, effective drug treatment of role (Kale et al., 2003; Poulsom et al., 2003; Duffield and brain tumors, epilepsy, and several mental disorders is lim- Bonventre, 2005; Huls et al., 2008b). Here, an overview of the ited (Fellner et al., 2002; Potschka et al., 2002; Lo¨scher and role of ABC transporters in tissue defense and organ regen- Potschka, 2005; Gerstner and Fine, 2007; Tate and Sisodiya, eration is given, with a focus on the role of P-gp and BCRP in 2007). The importance of transporters in the blood-brain these processes. Special attention is given to their potential barrier was emphasized in mdr1aϪ/Ϫ mice, which died from in regeneration of damaged nephron segments after acute the neurotoxic action of ivermectin, a known P-gp substrate, kidney injury. after treatment for mite infestation (Schinkel et al., 1995; Schinkel, 1997). Besides drug absorption and drug distribution, ABC trans- ABC Transporters in Tissue Defense porters also affect the excretion of drugs into the bile or Downloaded from The localization of ABC transporters in organs, with a urine. In the liver, ABC transporters are responsible for the barrier function, and the broad substrate specificities suggest elimination of xenobiotics and their metabolites into bile an important role in tissue defense. The efflux pumps are [P-gp, bile salt export pump (ABCB6), MRP2] or in the sys- determinants for the absorption, distribution, and excretion temic circulation (MRP1/3). More water-soluble drugs can be of drugs, xenobiotics, and their metabolites (Fig. 1). Entrance excreted into urine by the kidney, where ABC transporters in the systemic circulation is prevented by the apical expres- are localized along the apical membrane (P-gp, MRP2/4 and jpet.aspetjournals.org sion of ABC transporters in the intestine (Mao and Unadkat, BCRP) of proximal tubule cells. 2005), like P-gp and BCRP, and the action of these transport- The defense mechanism formed by ABC transporters un- ers leads to a decreased drug concentration in the liver. The der physiological circumstances is directed against accumu- liver is the major site of xenobiotic metabolism in the body, in lation of potentially harmful compounds. Interestingly, in a which enzymes, such as cytochrome P-450 (P450) family situation of organ damage or disease, changes in the expres- members, catalyze the oxidative metabolism of many drugs, sion levels of ABC transporters have been observed, probably eventually affecting both drug efficacy and drug toxicity to compensate for the increased load of harmful products of at ASPET Journals on April 2, 2015 (Schuetz et al., 1996). P-gp is able to mediate cellular efflux oxidative stress formed during an insult or to compensate for of P450 modulators, like rifampicin. Rifampicin induces the loss of efflux pumps in damaged tissues. In severe human CYP3A activity in a dose-dependent manner, thus a lower liver disease (primary biliary cirrhosis, cell necrosis, or Fig. 1. Tissue distribution of P-gp and BCRP. Dotted arrows indicate the direc- tion of efflux of substrates excreted by P-gp or BCRP. Both transporters are ex- pressed in the luminal membrane of the endothelial cells comprising the blood- brain barrier (1), where they protect the brain from toxic substrates; the choroid plexus within the brain (2); the apical membrane of epithelial cells of the mam- mary gland during lactation (BCRP; 3); the canalicular membrane of hepatocytes (4); the brush-border membrane of proxi- mal tubules (5), which mediates the ex- cretion into the urine; the apical mem- brane of the intestinal epithelial cells (6), which prevents the absorption of sub- strates into the human body; the syncy- tiotrophoblasts (7), and the side popula- tion within the bone marrow (8). P-Glycoprotein and BCRP in Tissue Repair 5 chronic hepatitis), MRP2 is down-regulated, but P-gp, BCRP, and Roninson, 1991), c-kitϩ stem cells (Sorrentino et al., MRP1, and MRP3 (ABCC3) were up-regulated, suggesting 1995), CD56ϩ natural killer cells, and CD8ϩ cytotoxic T cells protection against the accumulation of toxic bile constituents (Neyfakh et al., 1989; Chaudhary and Roninson, 1991; Drach and prevention of further liver damage (Ros et al., 2003a; et al., 1992; Klimecki et al., 1994). Vander Borght et al., 2006). A genetic defect in ABCC2 leads P-gp is capable of transporting many drugs and endoge- to mild hyperbilirubinemia called the Dubin Johnson syn- nous substrates. P-gp substrates are cationic or amphipathic drome. These patients show up-regulation of MRP3 in the in nature and mainly hydrophobic, indicating that they can liver (Corpechot et al., 2006).
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