The Cell - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 36

utilize the same transport pathway. These transport mechanisms may be modulated to
characterize and optimize the therapy. The individual variation in the responsiveness
to the therapy may be attributed to variability in the expression of these transporters
[11-121] .
Multidrug Resistance Protein—P glycoprotein
P glycoprotein (Pgp) drug transporter of the ABC superfamily is an ATP-powered
drug efflux pump, one of the first from the family to be identified. It has gained con-
siderable importance and scientific attention because of multidrug resistance linked
with its overexpression. The transporter includes two transmembrane units and two
cytoplasmic nucleotide-binding (NB) domains that bind and hydrolyze ATP. They
are expressed abundantly on epithelial cells exhibiting excretory functions as well as
the physiological barriers like blood-brain barrier and so on. Their high expression
in the barriers suggests a protective function against toxins. The Pgp does not exhibit
very high specificity and interacts with several nonpolar, weakly amphipathic com-
pounds, including natural products, anticancer drugs, and so forth. Apart from these
substrates, which are preferentially transported to the exterior by these transporters,
there is another category of substrates: modulators. The modulators reverse the Pgp
action by blocking their efflux action. This property has been exploited to maximize
therapeutic benefits of some drugs. In general, the structures of substrates or mod-
ulators do not possess any structural specificity that would allow interaction with
the protein. But most substrates are hydrophobic, become concentrated into lipidic
membranes, and present themselves to the protein. A hydrophobic vacuum cleaner-
type of action has been attributed to these proteins. They efflux out the hydropho-
bic substrates entering the membrane and prevent their cytosolic localization. They
have a very important role in determining the pharmacokinetics of several drugs
like anticancer drugs, HIV protease inhibitors, analgesics, calcium channel block-
ers, immunosuppressive agents, cardiac glycosides, anthelmintics, antibiotics, and
H2-receptor antagonists. The overexpression of the transporter has been attributed
to being an adaptation to the presence of toxins in the environment. However, large
interindividual variability is due to the presence of several isoforms of the proteins
[122-12] .
Multidrug Resistance Proteins of the ABCC Subfamily
The ABCCs/MRPs belong to ABC-type unidirectional efflux transporters for conju-
gated and unconjugated organic anions. The human ABCC (adenosine triphosphate
binding cassette transporter type C) subfamily consists of the nine MRPs, the cystic
fibrosis transmembrane conductance regulator (CFTR), and two sulfonylurea recep-
tors, SUR1 and SUR2. They exhibit two cytoplasmic nucleotide-binding domains
(NBDs) and two or three membrane-spanning domains (MSDs). They are mostly
localized in the liver, kidney, intestine, and blood-tissue barriers. The ABCC/MRP
transporters differ from Pgp, in amino acid sequence and substrate specificity. These
transporters have been implicated with conferring resistance to a large and diverse