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ASIA-PACIFIC JOURNAL OF CARDIOLOGY

REVIEW ARTICLE

Role of ABC Transporters in Cardiovascular Diseases
´ ˜ Joao Marcos A Delou1, Anibal G Lopes2 and Marcia AM Capella1,2 ´ ´ ´ Affiliations: 1Instituto de Bioquımica Medica and 2Instituto de Biofısica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

A B S T R A C T
Hypertension and atherosclerosis represent major causes of cardiovascular events. Both are chronic inflammatory disorders associated with an increased risk of mortality and morbidity. In the last few years, increasing evidence points to the involvement of ABC transporters in inflammation, hypertension, and atherosclerosis. The main ABC proteins related to these diseases are ABCA1, ABCB1, ABCC1, ABCG2, and possibly ABCG5 and ABCG8. Recent studies have suggested a direct participation of both ABCB1 and ABCC1 in the genesis of hypertension, by modulating plasma aldosterone disposition and tissue uptake or by modulating the hypertensive response to angiotensin II respectively. Moreover, some ABC transporters are known to transport several drugs to urine, including some antihypertensive drugs. This review presents a concise explanation about each member of the ABC protein superfamily and summarizes the recent findings regarding the relationship between these proteins and the inflammatory disorders that lead to cardiovascular events. Keywords: ABCA1, ABCB1, ABCC1, ABCG2, hypertension, atherosclerosis ´ Correspondence: Joao Marcos A Delou, Instituto de Biofısica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS—Bloco G, ˜ 21949-900—Rio de Janeiro, RJ, Brazil. Fax: +55-(21)2280-8193; e-mail: jmdelou@gmail.com

INTRODUCTION
Cardiovascular diseases are the main cause of death worldwide. Hypertension and atherosclerosis are both chronic inflammatory disorders associated with an increased risk of mortality and morbidity, and represent major causes of cardiovascular events, such as stroke, ischemia, and infarction. Hypertension is estimated to cause 4.5% of current global disease burden, and its prevalence is similar in both developing and developed countries [1]. According to a recent review, approximately 54% of stroke, 47% of ischemic heart disease, and 25% of other cardiovascular diseases worldwide can be attributable to high blood pressure [2]. In the last few years, increasing evidence has pointed to the involvement of ABC proteins in hypertension, atherosclerosis, and cardiovascular events. For example, ABCB1 and ABCC1, the two main ABC proteins first described in multidrugresistant (MDR) tumors, are known to physiologically transport several endobiotics, including hormones, and have recently been associated with hypertension [3, 4]. In addition, ABCB1 and ABCG2 are known to secrete a number of drugs to urine, including some antihypertensives [5, 6], and several ABC transporters are lipid transporters and seem to contribute to the development of atherosclerosis.

SEARCH STRATEGY AND SELECTION CRITERIA
Data for this review were identified by searching Pubmed, and references from relevant articles using the search terms ‘‘ABCA and atherosclerosis’’, ‘‘ABCA1 and atherosclerosis’’, ‘‘ABCA and hypertension’’, ‘‘ABCB and hypertension’’, ‘‘ABCC and hypertension’’, ‘‘ABCD and hypertension’’, ‘‘ABCE and hypertension’’, ‘‘ABCF and hypertension’’ and ‘‘ABCG and hypertension’’, ‘‘P-glycoprotein and hypertension’’, ‘‘MDR1 and hypertension’’, ‘‘MRP1 and hypertension’’, ‘‘BCRP and hypertension’’, ‘‘ABCA1 and hypertension’’, ‘‘ABCG2 and hypertension’’ were used. Papers published in English from 1980 to August 1, 2009 were included.

THE ABC SUPERFAMILY
The ATP binding cassette (ABC) superfamily is one of the largest families of proteins known, consisting of more than 3000 members with representatives from every kingdom of life. This superfamily comprises two types of proteins, the ABC transporters and the cytosolic ABC-ATPases. The majority of the ABC proteins are transmembrane transporters that actively translocate a wide range of substrates among cellular compartments using adenosine triphosphate (ATP) hydrolysis, whereas the cytosolic ABC-ATPases are a smaller group involved in the maintenance and repair of chromosomes and in protein synthesis. For further information, a good review on the subject was published recently [7].

OBJECTIVES
The aim of this review is to identify and summarize the recent findings about ABC proteins that might be involved in the genesis and/or maintenance of mainly hypertension, but also atherosclerosis, and therefore related to the global burden of cardiovascular diseases.
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The human ABC transporters
The human ABC transporters are integral membrane transporter proteins related to several cellular functions.
1 www.slm-asia.com

8]. e. Some substrates of two ABC transporters are presented in Table 1 [9–11]. The predicted structures of ABCA1. The human ABC transporters are active transmembrane proteins that use the cleavage of ATP to ADP+Pi in order to transport substances across the membrane. ABCD. for this reason. ABCA1 is the most studied protein in this family. Association of polymorphisms of ABCA1 and ROS1 with hypertension in Japanese individuals has been reported [19]. An increased frequency of ABCA1 polymorphism was observed in a sample of coronary artery disease cases in recent genome-wide association scans (GWAS) [23]. ABCE. Cdc42. and others. but lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of ischemic heart disease [22]. Each protein in these subfamilies is identified by a number positioned after the four letters that designate the subfamily. The five. ABCG2. ABCC1. which is not present in the cytosolic ABC-ATPases. resulting in a change from an arginine to a lysine at residue 219) was associated with a decreased risk of coronary artery disease in some European and American populations [25–29]. but not in two Japanese studies [30. 13]. and the glycosylations are indicated. In the last few years.slm-asia. it is the only ABC protein with a receptor-like signaling pathway. for instance. Schematic model of ABC transporters. Moreover. such as hormones. recently recognized as a major regulator of cellular cholesterol and phospholipid homeostasis (Figure 2). in humans. without pronounced effects on plasma lipids [24]. Wakefield +44(0)1924 369598 Rev 9.com Asia-Pacific Journal of Cardiology joc209093.0. and other protein kinases [15]. drugs. ABCF. the ATP active sites (NBD). which is the ATP catalytic site.225/W (Oct 13 2006) .g. although other extracellular and intracellular domains are common and very variable among transporters (Figure 1). ABCB1. Month 2009 2 www. no importer has been described in human cells so far. subdivided into seven subfamilies with names ranging from A to G. ABCC1. and it has been shown that ABCA1 expression is decreased in untreated hypertensive patients and normalized in patients receiving antihypertensive treatment [20]. protein kinase C [14]. and ABCG. toxins. lipids. some of these proteins have been associated with cardiovascular diseases. ABCC. it must present at least one cytoplasmic nucleotide binding domain (NBD). Mutations in ABCA1 predicted risk of ischemic heart disease in the Copenhagen City Heart Study Population [21]. the intracellular and extracellular loops. which features physiological deficiencies in high-density lipoprotein (HDL) and apolipoprotein E [16–18]. Although there are both importers and exporters in the ABC superfamily. It is constitutively expressed in several tissues and has recently been associated with atherosclerosis. 31]. APJOC 2009. usually against a concentration gradient. This polymorphism was previously associated with slightly higher HDL cholesterol and lower prevalence of coronary artery calcification in another study ABCA SUBFAMILY The ABCA subfamily is composed of at least 13 members mostly consisting of cholesterol and lipid transporters [7]. To be classified as an ABC transporter. It was also shown that the G1051A polymorphism (a G to A substitution at position 1051 in exon 7. two polymorphisms in the promoter region (the –565C/T and the –191G/C variants) were inversely associated with risk of coronary heart disease among healthy women. The substrates recognized by these transporters are numerous. always after the ABC letters: ABCA.Asia-Pacific Journal of Cardiology There are approximately 50 known human ABC transporters.or six-helix transmembrane domains. and ABCG2 are represented as members of each family of ABC transporters. and must present at least one extracellular transmembrane domain (TM). via Janis kinase 2 [12. peptides. exporter and a suggested apolipoprotein receptor.3d 23/11/09 20:40:43 The Charlesworth Group. ABCA1 is a cholesterol Figure 1. they are commonly referred to as efflux pumps [7. plant metabolites. Until now. ABCB. the protein must share some common characteristics. 000:(000). Mutations in the ABCA1 gene have been associated with Tangier disease..

NB0506. Transcriptional repression of the ABCA1 gene in macrophages www. Verapamil Antifungals Itraconazole. Lopinavir. Wakefield +44(0)1924 369598 Rev 9. Morphine Antiemetic Ondansetron [32]. Karenitecin (BNP1350). FK506. Rifampicin Anticancer Drugs Doxorubicin. UCN-01. and it was suggested that they could facilitate myocardial infarction in the Japanese population. A recent review was published concerning polymorphisms in the ABCA1 gene. Triglutamate Porphyrins Pheophorbide A. Midazolam. Lovastatin. ABCA1 is one of the major modulators of macrophage foam cell formation and atherosclerotic lesions [20. Daidzein. Sparfloxacin CNS Drugs Levomeprazine. Nitrofurantoin. Flavopiridol. Erlotinib. Hydrocortisone Steroid Dexamethasone Anxiolytics. Etoposide. Teniposide. Nelfinavir. Zidovudine Antibiotics Ciprofloxacin. Fosamprenavir. Doxorubicin. Paclitaxel. SN-38 (Irinotecan metabolite). the correlation was not significant [19]. 34. Diltiazem. Tipranavir Antibiotics Grepafloxacin.slm-asia. Cytarabine. Vinblastine. Diflomotecan (BN-80915). Last year. Cisplatin. Saquinavir. Domperidone Cardiac Drugs Digoxin.11 Antihistamines Terfenadine. Atazanavir. HDL cholesterol. Ripseridone Hormones Aldosterone. Flavin mononucleotide (FMN).0. 35].3d 23/11/09 20:40:47 The Charlesworth Group. Indinavir. and risk of ischemic heart disease in the general population [22]. 000:(000).com Asia-Pacific Journal of Cardiology joc209093. two polymorphisms in the ABCA1 gene were investigated. Erythromycin. Cladribine. Epirubicin. Mitomycin. Daunorubicin. Gimatecan. Protriptylene. it was observed that the T allele of the 2565 C/T polymorphism may increase risk for subclinical cardiovascular disease [32].ABC transporters in cardiovascular diseases Table 1. Methotrexate. and prooxidative properties commonly increased in hypertension) alters macrophage cholesterol homeostasis and promotes foam cell formation and atherosclerosis [36]. JNJ-7706621. Nelfinavir. Etoposide. Nefazodone Immunosupressive Agents Cyclosporine A. J-107088. Gefitinib. Posuvastatin Antidiabetic Glyburide Vitamins and cofactors Riboflavin (B2). On the other hand. Prednisolone. Actinomycin D. Mitoxantrone. Edevarone (metabolites). Quinidine. Daunorubicin. Cyclosporine A (CSA) stimulates the renal epithelial sodium channel by elevating cholesterol content in the membrane in 3 APJOC 2009. Talinolol. Coumestrol. Vindestine Anti-HIV Abacavir. Methadone. Ofloxacin. Menadione (K3). Month 2009 . Heterocyclic amines. Biotin (B7). GW1843. Docetaxel. CL1033. and it was shown recently that it is associated with a 5. Exatecan Mesylate (DX-8951f). Chlorin E6. Fluorouracil. Quercetin. however. Genistein Antihypertensive Olmesartan Antiplatelet Dipyridamole Antirheumatic Leflunomide Statins Pitavastatin. Antihistamines Cimetidine Phytoestrogens Resveratrol. Vincristine. Methotrexate. Pyropheophorbide A Substrates of ABCG210. Sulfasalazine Anticancer Drugs 9-aminocamptothecin. Teniposide. sedatives Amitriptyline. ABCB1 and ABCG2 Substrates: Examples of Endogenous and Exogenous Substances transported by ABC Proteins arranged in Classes Substrates of ABCB19 Anti-HIV Aprenavir. Estradiol.5% higher concentration of small HDL particles [33]. Methylprednisolone. Ritonavir. Topotecan. Norfloxacin. Bisantrene. Tomudex. Imatinib. Homocamptothecin. proliferative. Tacrolimus Opiates Fentanyl.225/W (Oct 13 2006) by the activation of angiotensin II receptor type 1 (a well-known receptor that mediates the classic pressor effects of angiotensin II but also the proinflammatory. Loperamide. suggesting that this allele may protect against subclinical cardiovascular disease. Celiprolol.

but ABCA1 apparently binds to APOA1. an ABCA1-mediated mechanism. and heart was significantly higher in ABCB1deficient mice [48]. A recent study showed that the combined action of ABCB1 and CYP3A5 gene polymorphisms was associated with postproximal tubular sodium reabsorption. not necessarily expressing all proteins.com ABCB SUBFAMILY The ABCB subfamily is one of the most studied families and is composed of at least 11 members with two TM and two NBD [7]. the regulation of its plasma disposition and tissue uptake is essential for the maintenance of blood pressure. The mechanisms for this transfer are not fully understood. Other ABC transporters might contribute to the establishment of atherosclerosis by other pathways. As enhanced ENaC activity is known to cause hypertension. Wakefield +44(0)1924 369598 Rev 9. it was shown that aldosterone activity in the plasma. but an increased expression of these genes in the duodenum. Also. We also showed. in a more recent study. and progesterone [43. Therefore. low-density lipoprotein (LDL). 000:(000). More recently. CsA significantly increased epithelial sodium channel (ENaC) open probability. and an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril [50]. but not in the kidney. whereas other polymorphisms of this gene were associated with 4 www. suggesting that aldosterone could be an endogenous regulator of this protein [39]. Confirming this hypothesis. but not ABCC1. 49]. ABCA1 and ABCG1 involvement in cholesterol homeostasis. and ileum. pregnane X receptor and constitutive androstane receptor have been reported to alter the expression of ABCB1. facilitating the development of atherosclerosis. the expression of ABC transporters can be regulated by several other hormones with either membrane or nuclear receptors. as proinflammatory mediator secretion by ABCC1 or ABCG2. This same group detected that some ABCB1 gene polymorphisms were related to altered glomerular filtration rate in Caucasians. APJOC 2009. Our results were further confirmed by another group that also observed a reduced expression of the abcb1a and abcb1b genes in the rat liver and kidney. The first publication concerning the involvement of an ABCB protein in hypertension was our study showing that a high-sodium diet diminished ABCB1 expression in rats [38]. and ABCG2 [45]. ABCC3. 44]. The schematic cell might represent a macrophage.0. it has been shown that the expression of abcb1a mRNA was induced in the murine small intestine. For example.3d 23/11/09 20:40:49 The Charlesworth Group.slm-asia. these data together suggest that CsA may cause hypertension by stimulating ENaC through a pathway associated with inhibition of ABCA1 and the consequent elevation of cholesterol in the cells [37]. the major protein component of HDLs. such as insulin [42]. eliciting the translocation of phospholipids and cholesterol across the plasma membrane bilayer. plasma aldosterone. ABCG1 promotes the efflux of cholesterol to mature HDL particles. ABCB1 expression is also induced by thyroid receptor in a pregnane X receptor-independent fashion [46. 47]. which leads to mature HDL particles. and very low-density lipoprotein (VLDL). that ABCB1. ABCA1 promotes the transfer of phospholipids to lipid-poor forms of apolipoprotein (APOA1). Hyperactivity of ABCA1 and/or ABCG1 might contribute to excessive cholesterol plasma concentrations.225/W (Oct 13 2006) . by treatment with the pharnesoid X receptor activators rifampicin and St John’s wort [41]. Because aldosterone plays an important role in the pathophysiology of numerous cardiovascular disorders. ABCC2. Other enzymes (not shown here) participate in the process. These data point to a possible role for ABCB1 in hypertension and were followed by additional studies in humans.Asia-Pacific Journal of Cardiology Figure 2. but also other cells. studies relating ABCB1 expression and its polymorphisms with plasma disposition and tissue uptake of aldosterone were carried out. including hypertension. jejunum. brain. We also showed that the mRNA expression of ABCB1 was diminished in adrenalectomized rats. plasma renin activity. estrogen [43]. is downregulated in peripheral blood mononuclear cells and in the kidneys of spontaneously hypertensive rats [39]. which expresses all four proteins. Month 2009 Asia-Pacific Journal of Cardiology joc209093. Indeed. suggesting that the regulation of this protein is tissue specific [40]. It is known that human ABCB1 transports aldosterone [5. forming the nascent HDL.

Another role for this protein is the secretion of several drugs. has a major role in blood pressure regulation. Moreover. No obvious correlation among these facts and any cardiovascular-related disease have been suggested until now. They are all functional homo. the results obtained by several authors. strongly suggest that ABCB1 contributes to blood pressure regulation. including an increase in intratumoral concentrations of doxorubicin without affecting C57BL/6 pharmacokinetics [55]. They also showed that the hypertension caused by angiotensin II was markedly blunted in ABCC12/2 mice. Therefore. it is clear that more studies are needed to fully understand the several apparent roles of ABCB1 protein in hypertension. strong enough to reverse ABCB1-mediated multidrug resistance (MDR) in melanoma cells in vitro and in vivo. This protein transports a wide variety of neutral and hydrophobic compounds and also several glutathione. The ABCE and the ABCF subfamily comprise the families of cytosolic ABC-ATPases with at least one and four members respectively. Human endothelial cells express ABCC1. and sulfate conjugates [56]. Besides its role in the plasma disposition of hormones related to hypertension. ABCD. Studies performed in knockout mice suggest that its first member. It is known that the production of reactive oxygen species is increased in hypertension and in oscillatory shear stress. it was shown that treatment with the ABCC1 inhibitor MK571 reduced vascular reactive oxygen species production. expression of several NADPH oxidase subunits. and this protein exports oxidized glutathione out of these cells. suggesting that this protein might be a new target for the therapeutic handling of hypertension. and protection against oxidative stress [54–59]. increasing the circulating concentration of adenosine and activating the adenosine receptor 2. which was prevented by the ABCC1 inhibitor MK571 and by ABCC1 small interfering RNA [60]. significantly improved endothelial function. preserved the intracellular reduced glutathione Nernst potential.com Asia-Pacific Journal of Cardiology joc209093. strongly suggesting that ABCC1 activity is essential for the hypertensive response to angiotensin II. ABCE1 is an RNase L inhibitor. and ameliorated atherosclerotic plaque generation in atherosclerosis-prone. but lack the TM. such as defense against xenobiotics and endogenous toxic metabolites. This is not a surprising result. and the levels of nitric oxide (NO) were greatly altered only in wild-type mice. erythrocytes. which occurs at points in the circulation predisposed to www. the inhibition of ABCC1 prevented the decline in intracellular reduced glutathione. and its binding and transport were not altered by the common variation C3435T in the ABCB1 gene [54]. to urine.slm-asia. although there has been no study relating ABCC1 genetic variants with blood pressure or hypertension in humans up to now. This same group showed that angiotensin II-induced hypertension increased oxidized glutathione export and decreased the vascular levels of reduced glutathione in wild-type but not in ABCC12/2 mice [61]. phosphorylated at two sites by CK2. most likely by influencing the synthesis and transmembrane transport of ouabain respectively [52]. Moreover. enhancing protein synthesis [64]. apolipoprotein -deficient mice on a highcholesterol diet. glucuronide. ABCC1 is involved in various physiological functions. therefore permissive for protein synthesis [63]. AND ABCF SUBFAMILY ABCC SUBFAMILY The ABCC subfamily is composed of at least 13 members with three TM and two NBD [7]. Moreover. Owing to its versatility and ubiquitous tissue distribution. 5 APJOC 2009. the ABCC1 protein. In a more recent study. atherosclerosis. Wakefield +44(0)1924 369598 Rev 9. In addition. suggesting that ABCC1 is also a potentially promising target for atheroprotective therapy [60]. The authors showed that the aortic endothelium-dependent vasodilatation was reduced in wild-type mice but was unchanged in ABCC12/2 mice after angiotensin II infusion. it was shown that murine myocardial and hepatic Abcb1a mRNA expression was significantly increased after 2 weeks of induced intermittent hypoxia [53]. among patients with essential hypertension.or heterodimeric transporters related to the peroxisomal transport of fatty acyl-CoA. through the regulation of plasma levels and tissue uptake of aldosterone and ouabain.3d 23/11/09 20:40:53 The Charlesworth Group. the altered endothelium-dependent vasodilatation caused by hypertension was ameliorated in ABCC1 knockout mice. it was reported that.225/W (Oct 13 2006) The ABCD subfamily is composed of at least four members with one TM and one NBD. losartan was shown to be a substrate for ABCB1. superoxide production. According to the authors. and modulate digoxin kinetics are related to circulating endogenous ouabain (a pressor hormone) and increased diastolic blood pressure. ABCF1 is a phosphoprotein that interacts with the eukaryotic initiation factor 2. Month 2009 . Very little is known about them [7]. alter the transport of many drugs. and reduced apoptosis caused by oscillatory shear. performed in either animals or humans. ABCE. leukotriene-mediated inflammatory responses. 000:(000). the commercial antiplatelet dipyridamole was identified as an ABCB1 modulator. as well as inflammation and hyperthermia. as it is already known that hypoxia is a strong stimulus for ABCB1 expression. suggesting that the ABCB1 gene is related to renal function in the general population [51]. This year. They present two NBD. possibly via the renin–angiotensin–aldosterone system. including antihypertensives. It acts via inhibition of adenosine uptake into platelets. In view of the results summarized above.0. It has been shown that oscillatory shear stress caused a strong export of oxidized glutathione. and endothelial cells. polymorphisms in the ABCB1 gene that influence its expression. For instance. the same authors showed that angiotensin II triggers the release of leukotriene C4 (a proinflammatory eicosanoid) in vascular smooth muscle cells via ABCC1 [62].ABC transporters in cardiovascular diseases renal function and hemodynamics in Africans. ABCG SUBFAMILY The ABCG subfamily is composed of at least six members with one TM and one NBD [7].

it has been shown that ABCG2 is involved in body regulation of menadione (vitamin K3). and the decreased lifespan of salt-loaded. As discussed above. This gene variant had previously been associated with angiographically defined severe coronary artery disease in two case–control studies [69]. Month 2009 6 arteries [77. but the uptake of its substrate rhodamine 123 was not affected by any of the cytokines [82]. xanthomas. widely used in the treatment of patients with congestive heart failure. namely stroke and coronary artery disease. For example. several studies have focused on the contribution of genetic polymorphisms of transport proteins to interindividual variability in the efficacy and safety of cancer therapy [84. although this mutation does not segregate with hypertension [81]. As with hypertension. This increased expression led to a diminished absorption of digoxin. It has been shown that the expression of ABCB1 in the intestine was increased by the aldosterone antagonist spironolactone [86]. antiplatelet. associations between both D19H and T400K polymorphisms in the ABCG8 gene and increased atherosclerosis were recently identified in a large cohort study of 2012 patients with heterozygous familial hypercholesterolemia [75]. The reasons for altered expression and/or activity of such transporters vary from gene polymorphisms to modulation by endogenous substances. to adequate endothelial-induced vasorelaxation. is most prominently characterized by hyperabsorption and impaired biliary elimination of dietary plant sterols. Sitosterolemia. a possible consequence of a decreased renal tubular elimination of digoxin [90]. Abcg12/2. and coronary APJOC 2009. spontaneously hypertensive rats (SHRSP) treated with a phytosterol-rich diet [79]. A missense mutation in Abcg5 confers sitosterolemia in both SHRSP and their control Wistar–Kyoto (WKY) rats [80]. which is transported by ABCB1 in the intestine and liver [87]. little is known about the influence of such proteins and their polymorphisms for the effectiveness of antihypertensive therapy. it has been shown that ABCA1 and ABCG1 expression is decreased in untreated hypertensive patients.0. which is necessary for the production of prothrombin and other blood clotting factors in humans [71]. was identified as a glutathione-dependent substrate of ABCC1. and it is well established that age and hypertension are the most powerful risk factors for stroke [72. Decreased expression of both intestinal Abcg5 and Abcg8 has also been proposed to explain the increased systolic blood pressure. whereas normal individuals absorb less than 1–5%. Both Abcg12/2 and Abca12/2Abcg12/2 mice fed with a highcholesterol diet accumulated diet oxysterols in endothelial cells and had increased atherosclerosis [65]. Homozygotes of the Val allele of ABCG2 were at higher risk of stroke than carriers of the Met allele. Because there is no study relating a direct role for ABCG2 in the genesis of hypertension. it was found that a single nucleotide polymorphism of ABCG2 (Val12Met) was associated with increased risk of ischemic stroke in both white and black participants [68]. ROLE OF ABC TRANSPORTERS IN DRUG UPTAKE AND DISPOSITION Besides their roles in the genesis and maintenance of hypertension and atherosclerosis. It has been proposed that interindividual variability in drug response and adverse drug reactions are related to alterations in the ABC membrane transporters. the earlier onset of stroke. 78]. and Abca12/ Abcg12/2 mice showed that Abcg1 expression in endothelial cells contributes greatly to endothelial nitric oxide synthase (eNOS) maintenance in its active dimeric form and. 000:(000). These cytokines also significantly reduced the ABCG2 activity as assessed by mitoxantrone uptake experiments. In addition. several pharmacokinetic studies have demonstrated the importance of some ABC transporters in limiting oral drug uptake and disposition. and vasodilator properties. tendons. the incidence of stroke is increasing in people living in both developed and developing countries. www. an electrophilic derivative of linoleic acid that has anti-inflammatory. 85].3d 23/11/09 20:40:53 The Charlesworth Group. 74]. it seems that the Met variant of the ABCG2 protein has a protective function in the vascular endothelium. Wakefield +44(0)1924 369598 Rev 9. and their expression is normalized in patients receiving antihypertensive treatment [20]. evidence obtained recently in two studies is consistent with a correlation between the ABCG2 polymorphisms and the leading causes of morbidity and mortality in hypertensive patients. it has been shown that the Met variant of ABCG2 has a lower transport activity and altered pattern of localization when compared with the Val variant [70]. an inhibitor of both ABCB1 [88] and ABCC1 [89]. ABCG2 mRNA levels were significantly reduced by interleukin (IL)-1b. verapamil. TNF-a also increased protein expression of ABCB1.slm-asia. or phytosterolemia. IL-6. On the other hand. It is a recessive disorder in which patients retain 15–20% of dietary plant sterols. stroke-prone. Although in the last few years. was shown to increase plasma digoxin concentration. to target organs. more studies relating ABCG2 with stroke and coronary artery disease and its role in vitamin K regulation are necessary in order to better understand this association. and it has been attributed to mutations in either the ABCG5 or the ABCG8 genes [71. consequently. ABCB1 and ABCG2 are differently modulated by proinflammatory cytokines. and tumor necrosis factor (TNF)-a. including several antihypertensive drugs. but significantly increased after TNFa treatment. which might also suggest it as a glutathione-dependent substrate of other ABCCs and/or also ABCG2 [83]. Also. 73]. 2 ABCG2 expression is modulated by a functional steroidbinding element present in its promoter [66] and by progesterone receptors A and B [67].225/W (Oct 13 2006) . a study with Abca12/2. Sitosterolemic patients develop premature atherosclerosis [76]. In humans. and premature coronary heart disease as a result of sterol deposition in the skin. On the other hand. Therefore. ABCB1 mRNA levels were slightly reduced by IL-6. affecting chemosensitivity and drug resistance. Interestingly. nitrolinoleic acid. In a recent cardiovascular health study. In humans.com Asia-Pacific Journal of Cardiology joc209093. the toxicity of the interaction between quinidine and digoxin was shown to be attributed to the inhibition of ABCB1 [91].Asia-Pacific Journal of Cardiology In 2008.

such as digoxin–carvedilol or cyclosporine–carvedilol. 103]. it has been shown that talinolol (a b1-adrenoceptor selective antagonist) inhibits the ABCB1-mediated transport of digoxin [95] and that celiprolol (a b1-adrenoceptor selective antagonist with slight a2-agonist action) and acebutolol (a b1adrenoceptor selective antagonist) are substrates for ABCB1 [96–98]. International Society of Hypertension. However. but not metoprolol [99]. Homolya L. Vlaming ML. 7 APJOC 2009. Kamiyama E. and cytokine dispositions in hypertensive individuals. Jones PM. and propranolol. ABCC2. 1992. carvedilol. and this information may help in the development of new drugs. aliskiren presented no clinically significant drug interaction with digoxin (an ABCB1 substrate) [101. and valsartan. the multidrug resistance-associated protein 1 (MRP1/ABCC1). a b-adrenoceptor antagonist with vasodilating activity used for the treatment of hypertension and coronary artery disease [92]. it was showed that aliskiren.35:2166–2176.371:1513–1518. A significant inhibition of polarized transport of ABCB1 in CaCo-2 monolayers was observed for bisoprolol. the observed interaction between CYP3A5 and ABCB1 genes and urinary sodium excretion in humans [50] suggests a new pathway for blood pressure regulation and has important implications regarding the response to antihypertensive treatment. 2002. especially in cancer. ABCC2. 2008. Hirai M. may have major implications. Sparreboom A. Global burden of blood-pressure-related disease. Month 2009 . aldosterone. Lawes CM. 7.47:515–531. Wakefield +44(0)1924 369598 Rev 9. was shown to reverse ABCB1-mediated MDR to anticancer drugs in tumor cells in vitro [93]. For example. Physiological and pharmacological roles of ABCG2 (BCRP): recent findings in Abcg2 knockout mice.21:1983–1992. carvedilol. O’Mara ML. a highly selective angiotensin II type 1 receptor antagonist. 10. metoprolol. J Hypertens. NCBI. et al. Jarugula V. Pal D. 000:(000). Pharmacogenomics. Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan.and CYP3A4-mediated drug-herbal interactions. 4. 9. both atorvastatin and ketoconazole (known ABCB1 inhibitors). is a substrate of ABCC2. George AM. these data strongly suggest that ABCB1 is a determinant of bisoprolol and carvedilol disposition in humans and that the inhibition of its activity possibly contributes to drug interactions. Okamura N. Human P-glycoprotein transports cortisol. Dean M. if confirmed in humans. MDR. maintenance. the possible altered expression of ABCB1 observed in hypertensive rats [38–40]. Pharmacogenomic importance of ABCG2. significantly increased exposure to aliskiren [101]. Yamada A. Clin Pharmacokinet. including a possible contribution to the reduced immune function and to altered drug. For instance. but not progesterone. the diuretic furosemide was shown to be transported by ABCC1. Portrait of multifaceted transporter. and that this may be related to its relatively low bioavailability [6]. REFERENCES 1. Over the past two decades. Programa de Apoio aos Nucleos ´ ˆ de Excelencia. Lancet. and treatment of hypertension and atherosclerosis is just beginning to be established.34(10):520– 31. Bethesda. Hydrochlorothiazide. Lagas JS. 2007. Vander Hoorn S. Pflugers Arch. recent results indicate that excessive dietary sodium ingestion greatly contributes to resistance to antihypertensive treatment [105].9(8):1005–1009. Dieterich HA. suggesting that this effect of carvedilol was independent of its action on b-adrenoceptors. Howard D. Moreover. 2009. Programa de Oncobiologia/Fundac˜o Ary Frausino ¸a ´ ˆ para Pesquisa e Controle do Cancer.225/W (Oct 13 2006) 8. The Human ATP-Binding Cassette (ABC) Transporter Superfamily. Bakos E. 3. In addition. However. and ABCC4 [102.3d 23/11/09 20:40:54 The Charlesworth Group. 11. et al. ABC transporters: a riddle wrapped in a mystery inside an enigma. but the co-administration of aliskiren with ABCB1 inhibitors should be not recommended. and dexamethasone. Several other drugs used in the treatment of hypertension are substrates or inhibitors of ABC proteins. This interaction was confirmed in patients receiving cyclosporine treatment after cardiac transplants in combination with carvedilol. hormone. Maeda K.78(18):2131–2145. These observations suggest that co-administration of aliskiren with other ABCB1 substrates will probably not lead to harmful interactions. drug toxicity and efficacy. 2009 Oct. as well as to harmful drug interactions. our understanding of the importance of ABCA1 to cholesterol homeostasis is very recent. 2008. 2. olmesartan. MD: National Library of Medicine (US). Rodgers A. Life Sci. is an ABCC2 substrate [104]. and its prodrug olmesartan medoxomil seems to be a substrate for ABCB1. 2006. a selective antagonist of the angiotensin II AT1-receptor. Collectively.0. Vaidyanathan S.267: 24248–24252. Ueda K. as the b1-adrenoceptor selective antagonists propranolol. Schinkel AH. and Conselho Nacional de Desenvolvimento Cientıfico ´ e Tecnologico. Whitworth JA. 102]. Adv Drug Deliv Rev. J Biol Chem. Mitra AK. Recently. several studies have focused on the clinical implications of genetic variations in drug transporters. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. when used at the maximum recommended dose. the first drug in a new class of renin inhibitors approved for the treatment of hypertension. but is increasing extremely fast. Also. This effect is not common to all b-adrenoceptor antagonists. 2001. CONCLUSIONS AND PERSPECTIVES Although initially the ABC proteins have been extensively studied in other diseases. 6. The involvement of ABC proteins in the genesis. Clinical pharmacokinetics and pharmacodynamics of aliskiren. In the last few years. Disclosure: The authors declare no conflict of interest. 2008. Dole WP. but not for metoprolol and sotalol [100]. Drug Metab Dispos.61(1):14–25.453: 621–641. Trends Biochem Sci. Cusatis G. and atenolol did not affect ABCB1mediated MDR [94].slm-asia. their importance to body homeostasis and their role in several cardiovascular disorders is progressively being revealed. pharmacogenetic research into human drug-metabolizing enzymes has improved our knowledge concerning drug interactions and individual susceptibility to www. 2003. 2007. and ABCG2 [5]. Funding: Our studies have been supported by grants from ` Fundac˜o Carlos Chagas Filho de Amparo a Pesquisa do Estado do ¸a Rio de Janeiro. is an ABCB1 substrate. a diuretic used worldwide. a novel angiotensin II type 1 receptor antagonist. resulting in unusual susceptibility to exogenous or endogenous toxins.com Asia-Pacific Journal of Cardiology joc209093.ABC transporters in cardiovascular diseases In contrast. is a substrate for ABCC4 [102]. Brazil. 5.

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