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Current Topics in Medicinal Chemistry, 2009, 9, 119-129
119
ABC Pumps and Their Role in Active Drug Transport
Nicola A. Colabufo*, Francesco Berardi, Marialessandra Contino, Mauro Niso and Roberto Perrone
Dipartimento Farmacochimico, Università degli Studi di Bari, via Orabona 4, 70125 Bari, Italy
Abstract: Pharmacokinetic limitations affect drug bioavailability determining the loss or the reduction of the
pharmacological effects. The Gastro Intestinal tract (GI) and the Blood Brain Barrier (BBB) are the most important
restrictive and selective physiological lines of defense of the organism. Although several parameters such as LogP, LogD
and Ka have been extensively employed for determining drug bioavailability, the active transports, present in these
biological barriers, play an important role for dosing and limiting cell drugs concentration. In particular, ATP Binding
Cassette (ABC) transporters are involved in the active transport both in GI and BBB. Their strategic activity and
biochemical and pharmacological role are herein treated.
Keywords: Blood brain barrier, ABC transporters, P-glycoprotein, MRPs, drug absorption and disposition.
INTRODUCTION
The therapeutic effect of many drugs is due to their
ability to cross cellular barriers for targeting the biological
sites. Usually it is accepted that lipophilic drugs can cross
these barriers in the absence of specific carriers because they
freely diffuse across the plasma membrane whereas
hydrophilic and charged compounds employ transporter
mechanisms to cross cell membranes. This is only a first
aspect of the question but another important aspect involves
the efflux of these drugs by active transporters; they
modulate the absorption and the accumulation of drugs and
toxic substances into the cells. In this paper we discuss the
critical aspects related to drug efflux by ABC transporters
considering the two major physiological barriers involved in
drug-transport ABC-mediated: the Gastro Intestinal tract
(GI) and the Blood Brain Barrier (BBB).
ACTIVE
TRACT
TRANSPORT
IN
Apical
1
2
Basolateral
GASTROINTESTINAL
Oral drug absorption from the intestine is a function of
different drug parameters: a) solubility in GI fluids; b)
metabolic stability; c) permeability [1,2]. Therefore, these
parameters modulate the oral bioavailability of drugs into the
systemic circulation. Drug absorption across the intestinal
membrane is due to passive and active absorption [3].
Passive absorption occurs through the cell membrane of
enterocytes (transcellular way) or through the tight junctions
between the enterocytes (paracellular way) as depicted in
Fig. (1).
Active absorption can be carrier-mediated or a facilitated
diffusion. Lipophilic molecules are absorbed through the
intestinal epithelium by passive diffusion whereas hydrophilic molecules by a carrier-mediated process. Some small
hydrophilic compounds are transported through the
paracellular junction [1]. As a first step transcellular
*Address correspondence to this author at the Dipartimento Farmacochimico, Università degli Studi di Bari, Via Orabona, 4, 70125, Bari, Italy;
Tel: +39-080-5442727; Fax: +39-080-5442231;
E-mail: [email protected]
1568-0266/09 $55.00+.00
365
Fig. (1). Transcellular (1) and paracellular (2) intestinal absorption.
absorption involves the crossing of the apical membrane
from lumen to blood. After transport across the cytosol, the
drug overcomes the basolateral membrane reaching the
blood. Usually, hydrophilic drugs employ the same carriers
of nutrients and micronutrients whereas lipophilic molecules
employ passive transcellular absorption [1,4] (Fig. (2)).
Active efflux pumps, belonging to ABC transporters such
as P-gp and MRP2, are localized on the apical membrane.
These transporters can extrude drugs back into the lumen [58] with the aim of dosing the absorption and the
accumulation of drugs and toxic substances into the cells and
of facilitating the intestinal clearance of compounds present
in the blood (Fig. (3)).
ABC transporters efflux unmodified drugs and/or drugs
metabolites as substrates (Fig. (4)) when these compounds
interact with cytochrome P450 (Phase I) and with
conjugating enzymes (Phase II). Intestinal CYP3A4, the
most important cytochrome isoform involved in first pass
© 2009 Bentham Science Publishers Ltd.
120 Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 2
Colabufo et al.
SHM
LM
HM
1
2
3
Apical
SHM
Small Hydrophilic Molecules
HM
LM
Lipophilic Molecules
HM
Hydrophilic Molecules
Basolateral
SHM
LM
HM
Fig. (2). Paracellular (1), facilitated diffusion (2); carrier-mediated (3) intestinal absorption.
Apical
ABC
trasporter
1
ABC
trasporter
2
Basolateral
Fig. (3). Intestinal absorption modulated by ABC transporters to regulate cell drug accumulation (1) and to facilitate intestinal clearance (2).
metabolism, regulates the systemic availability of many
orally administered drugs. It has been reported that in small
intestine P-gp and CYP3A4 are localized on the villus tip of
enterocytes [7,9-12] where they synergistically act. Each of
the two metabolic phases can transform the metabolized
drugs into efflux pumps substrates [13].
366
ATP-BINDING CASSETTE (ABC)
GASTROINTESTINAL TRACT
FAMILY
IN
ABC subfamilies involved in intestinal transport are the
MDR subfamily, including MDR1, MDR3, BSEP, and the
MRP subtype, including MRP1-9 [2]. Moreover, also BCRP
ABC Pumps and Their Role in Active Drug Transport
Apical
Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 2
1
121
2
ABC
trasporter
Metabolising
enzymes
Metabolising
enzymes
Basolateral
Fig. (4). Modified drug absorption (1) and elimination (2).
is considered to be involved in the intestinal transport
[14,15].
paclitaxel [24] although the relationship between MDR3 and
multidrug resistance has to be demonstrated yet.
ABCB SUBFAMILY
BSEP (Bile Salt Export Pump)
P-glycoprotein
ABCB1, also known as P-gp, displays a large spectrum
of transported substrates in particular lipophilic and cationic
compounds although P-gp potential substrates preferentially
are anticancer agents, antibiotics, antivirals, calcium channel
blockers, and immunosuppressive agents. At this list of
biologically active compounds food and vegetables should
also be added [3,16].
P-gp is highly localized in kidney, adrenal gland, liver,
colon and lung, and also as basal level in prostate, skin,
spleen, heart, skeletal muscle, stomach and ovary and in
BBB [17,18]. This membrane apical localization plays a
critical role in the efflux of xenobiotics and toxins into the
intestinal lumen, bile, urine, and blood [7,11,12,18-20]. The
apical P-gp expression allows the efflux transport of several
anticancer drugs both from basolateral to apical and from
blood to lumen modulating their oral bioavailability.
MDR3
MDR3 has been firstly identified as a canalicular
phospholipid translocator [21,22] and the studies to investigate its role were carried out in human MDR3 gene
mutation experiments observing its involvement in pathologies that results in phospholipid secretion by the liver and
high serum -glutamyltransferase levels [23].
MDR3 protein effluxes several drugs such as digoxin,
and several antineoplastic agents such as vinblastine, and
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BSEP, also known as Sister of P-gp (SP-gp) for its close
sequence homology with P-gp, was first cloned from porcine
liver [25]. BSEP mediates bile acid transport across the
canalicular membrane of hepatocytes downregulating
intracellular bile acid concentrations and regulating the
enterohepatic circulation of bile acids.
Although BSEP is a Sister P-gp protein, it is not involved
in the efflux of several chemotherapeutic agents that are
specific P-gp substrates. Consequently, BSEP in drug disposition is less involved than its close relative P-gp.
ABCC SUBFAMILY
MRP1
MRP1 (ABCC1) is localized in high levels in intestine,
brain, kidney, lung, and testis, and lower expression was
found in liver [26-29]. MRP1 is present in basolateral membranes of polarized epithelial cells, renal distal and collecting
tubules [30], and liver [31,32]. Although MRP1 involvement
in the intestinal drug disposition is not completely clarified,
its ability to confer resistance to antineoplastic drugs has
been demonstrated [33].
MRP1 protein effluxes several conjugated metabolites,
such as glutathione conjugates (leukotriene C4 and 2,4dinitrophenyl-S-glutathione), bilirubin glucuronides, estradiol-17--glucuronide, and dianionic bile salts [34-37]
indicating its involvement in detoxification of endogenous
metabolites.
122 Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 2
Colabufo et al.
MDR1 subfamily
Out
1
2
3
4
5
6
7
8
9
10
11
12
In
NH2
NBD 2
NBD 1
COOH
MRPs subfamily
NH2
Out
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
In
NBD 2
NBD 1
COOH
BCRP transporter
Out
1
2
3
4
5
6
In
NBD
COOH
NH2
Fig. (5). ABC transporters in GI tract.
MRP1 localization at basolateral level suggests that this
protein protects cells through the efflux of substrates into the
blood. Indeed, MRP1 is responsible for the elimination of
toxins and this action is more effective when it is coupled
with apical P-gp. Both MRP1 and P-gp expression was
higher in tumour tissues treated with chemotherapeutic
agents than in untreated tumours [38].
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MRP2
MRP2 (ABCC2), originally identified in human liver as
the canalicular multispecific organic anion transporter
(cMOAT) [39], is highly expressed in liver, intestine, and
kidney tubules [6,40,41]. MRP2 is localized at the apical
membranes of these tissues [6,40,42,43]. This pump
ABC Pumps and Their Role in Active Drug Transport
Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 2
transports conjugated and unconjugated anionic compounds
into bile and the specific substrates of this pump are
equivalent to MRP1 substrates. Moreover, as reported for
BSEP, MRP2 mediates bile acid secretion from the
hepatocytes. Differing from BSEP, MRP2 transports only
sulphated bile salts such as taurochenodeoxycholate-3sulphate and taurolithocholate-3-sulphate, but not monoanionic bile salts such as taurocholate [44]. Considering the
transported substrates, MRP2 contributes to the detoxification by secreting metabolites into the bile. MRP2 protein
also transports potentially toxic or beneficial dietary
constituents, such as flavonoids [8,45].
It has been hypothesized that the MRP2 pump is coexpressed with enzymes involved in Phase II metabolism,
because of the fact that this pump transports several
conjugated compounds. Among Phase II metabolizing
enzymes, Glutathione-S-transferase catalyses the conjugation
of glutathione to a range of electrophilic compounds then
exported by MRP transporters. Glutathione-S-transferases
are reported in several isoforms (, μ, , , , and
microsomal). Human GST -isoform expression is reported
in duodenum and small intestine decreasing from proximal
to distal small intestine, and from small intestine to colon
[46]. Moreover, a co-expression of MRP2 with other Phase
II metabolizing enzymes such as UDP-glucuronosyltransferases (UGT) has been reported. These enzymes catalyse
the conjugation of glucuronic acid to nucleophilic CYP3A4.
Therefore, given the co-expression with Phase II metabolizing enzymes, is possible to assert that MRP2 plays a
synergistic role in intestinal drug detoxification and
excretion.
MRP3
The presence of MRP3 (ABCC3) has been reported in
liver, small intestine and colon and, differently from MRP2,
its expression is high in the ileum and colon [47]. MRP3 is
localized to the basolateral membrane [48] showing a similar
substrate specificity with MRP2 and BSEP, because it
effluxes bile salts [49,50]. The affinity for bile salts, and its
expression in the intestine suggests a possible involvement
of MRP3 in bile salt uptake.
MRP4
MRP4 (ABCC4) has been detected in jejunum, kidney,
brain, lung [51-54] and it is structurally more similar to P-gp
than to the other "typical" MRP transporters. MRP4 is
expressed on the apical membranes of human renal proximal
tubule cells [53] and basolaterally in tubuloacinar cells of the
prostate gland [55]. MRP4 transports folic acid, folinic acid
(leucovorin), methotrexate [56], cAMP, cGMP, estradiol-17-glucuronide, and bile acids [57-60] and its physiological
role regards prostaglandin-E cellular release. The apical
localization both in kidney and in the intestine suggests that
MRP4 is involved in biliary secretion of nucleoside phosphonate analogues and it limits their intestinal absorption
contributing to their poor oral bioavailability.
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123
MRP5
MRP5 (ABCC5) is structurally similar to MRP4 and it is
reported basolaterally in colon, liver, kidney, skeletal muscle
[51,61] and brain [29]. MRP5 does not confer resistance to
antineoplastic drugs and in the meantime there is no
evidence of intestinal drug disposition MRP5-mediated.
MRP6
MRP6 (ABCC6) is highly expressed in kidney, liver,
duodenum, colon, brain, and salivary gland [29,62,63]. It
was hypothesized that MRP6 mediates the transport of
several natural cytotoxic agents that are also substrates for
MRP1-3, including etoposide, doxorubicin and cisplatin
[64].
MRP7-9
Recent reports indicate that MRP7 (ABCC7) is detected
in liver, kidney, colon, spleen, skin, stomach, and testis [65]
while MRP8 (ABCC8) is highly expressed in breast cancer,
and at moderate levels, in normal breast, testis, and, at low
levels, in liver, brain, and placenta [66]. Two variants of
MRP9 (ABCC9) have been identified, one subtype reported
in breast cancer, normal breast, and testis, and the other in
brain, skeletal muscle, and ovary [67]. Although MRPs7-9
are not functionally classified, their important roles in drug
resistance and drug efflux have been hypothesized.
ABCG SUBFAMILY
BCRP
BCRP (ABCG2) is an ABC half-transporter expressed in
breast, ovary, small intestine, colon, and liver [68,69]. BCRP
mediates secretory transport of drugs in polarized cancer cell
lines of breast, colon and stomach [70] and has a large effect
on the oral bioavailability of the anticancer drugs. Since the
in vivo data demonstrate that BCRP effluxes the same
substrates as P-gp [71], these findings suggest BCRP as halftransporter compared to P-gp in regulating drug absorption
and disposition. On the other hand, BCRP pump has six
transmembrane domains with respect to twelve transmembrane domains of P-gp.
ABC TRANSPORTERS IN GASTROINTESTINAL
TRACT AND IN PERIPHERAL REALATED ORGANS
In Fig. (6) ABC transporters are shown displaying for
each tract or organ with their basolateral or apical localization. In the enterocytes MRP1 and MRP3 are localized at
the basolateral level while MDR1, MRP2 and BCRP act at
the apical level. In the proximal tubular cells of kidney,
MDR1 and MRP2 are localized at the apical membrane.
Moreover, MDR1, MDR3, BSEP, BCRP and MRP2 are
present at the canalicular membranes and can secrete
compounds modified or unmodified, into the canaliculus and
ultimately into the bile.
124 Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 2
Colabufo et al.
A
Apical / Lumen
P-gp
MRP2
BCRP
Enterocyte
MRP3
MRP1
Basolateral / Blood
Intestinal villus
B
Apical
P-gp
MRP2
Proximal tubular cell
Basolateral
Nefron
370
ABC Pumps and Their Role in Active Drug Transport
C
Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 2
125
canalicular membrane
MDR1/P-gp
MRP1
MRP2
MDR3
Canaliculus
MRP3
BCRP
BSEP/SP-gp
Blood
Blood
Hepatocytes
Fig. (6). Localization of some ABC transporters in enterocytes (A), in proximal tubular cells (B) and in hepatocytes (C).
ACTIVE TRANSPORT IN THE BLOOD BRAIN
BARRIER
Drug availability into the brain is modulated by physical
barriers such as Blood Brain Barrier (BBB) and Blood
CerebroSpinal Fluid Barrier (BCSFB). BBB and BCSFB are
different in location, size, morphology, and function [72-74].
BBB regulates and preserves the brain acting as a physical
and metabolic barrier. The presence of tight junctions
(zonulae occludens) [75] between endothelial cells and the
lack of fenestrae and pinocytotic vesicles in the cerebral
arterioles, capillaries, and endothelium venules modulate
brain uptake. BCSFB is formed by the choroid plexus
epithelial cells which are connected by tight junctions,
whereas the capillaries are fenestrated.
BBB modulates molecules access to the brain by two
processes: 1) passive diffusion or 2) active transport [72].
The first process mediates lipid and small nonpolar
molecules access while the second process is mediated by
several membrane transporters modulating the influx or
efflux of various essential substrates (electrolytes, nucleosides, amino acids, and glucose). Although lipophilicity has
been considered a facilitating aspect to permeate the lipid
bilayer, several molecules and drugs display lower brain
permeability despite a favourable lipophylicity.
The molecules access trough BBB is performed by two
possible mechanisms: (i) carrier-mediated transport, (ii)
active efflux transport. Usually, CNS penetration of small
371
molecules is modulated by carriers and/or active transporters
[76,77] whereas large molecules permeation can be receptormediated. Carriers prevalently mediate the influx of
substrates from brain to blood, although some carriers can
modulate the opposite flux while the active transport
modulates the efflux from brain to blood.
Molecules access from brain to blood is a process
mediated by two transporter families including an energydependent and energy-independent transporters [74]. ABC
transporters are energy-dependent system and they are
prevalently localized at the luminal membrane. Solute
Carrier (SLC) transporters are energy-independent systems
and are localized at the abluminal membrane of the brain
capillary endothelial cells [78,79].
ATP-BINDING CASSETTE (ABC) FAMILY IN BBB
P-glycoprotein
High levels of P-gp are reported in the luminal membrane
of the endothelial cells constituting BBB, BCSFB, and
blood-testis barrier [76,80-82]. Such strategic localization
gives P-gp a physiologically crucial role. P-gp links drugs in
the core of the lipid bilayer and flips them into blood [83]. Pgp exerts a protective function in BBB; for example, recent
results reported a significant correlation between Parkinson’s
disorder induced by pesticides and ABCB1 gene polymorphism (C3435T). The mutation of this gene increases the
toxic effects of pesticides and of other toxic xenobiotics
126 Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 2
Colabufo et al.
usually effluxed by P-gp. In Alzheimer’s disease, the
expression of P-gp in blood vessels contributes to the
accumulation of -amyloid: the first step to diagnose this
pathology suggesting a P-gp involvement in Alzheimer’s
disease [84,85]. Moreover, the differences in P-gp expression and dislocation in the brain area could be correlated to
other diseases such as epilepsy. In this case, P-gp is present
both in endothelial cells and in perivascular astrocytes [86].
Furthermore, P-gp is highly expressed in many tumors [87].
MRPs
MRPs in particular are involved in the extrusion of
conjugated xenobiotics and the mostly representative
transporter of this family, MRP1, is expressed at the luminal
site of the brain capillaries. Evidence of the presence of
MRP3 and MRP5 proteins at the BBB is reported [88].
CONCLUSIONS
The active transporters play a crucial role in drug
bioavailability and disposition in several compartments such
as BBB, BCSFB and GI. The study and the characterization
of ABC transporters give perspectives and a new address in
drugs discovery. These findings should be addressed by the
medicinal chemist in the plan of new drugs optimizing their
pharmacodynamic properties by strategies consistent with
pharmacokinetic requirements for overcoming biological
barriers. Therefore, more predictive biological assays are
needed to assess the interaction of drugs with active transporters in order to limit the discrepancies between the
encouraging pharmacodynamic in vitro profile and the
results found in the in vivo assays because of the involvement of active transporters.
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Received December 3, 2008
Accepted January 21, 2009
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