Biomedical Engineering Reference
In-Depth Information
10.1. P-GLYCOPROTEIN GENE FAMILY
P-Glycoprotein (Pgp) was one of the first members of the adenosine triphosphate
(ATP)-binding cassette (ABC) superfamily to be studied. Overexpression of Pgp was
linked to multidrug resistance (MDR) in mammalian cell lines and human cancers,
evoking intense interest first from molecular and cell biologists, and later, when puri-
fied Pgp became available, from biochemists and biophysicists. Today, this fascinating
protein, which is proposed to operate as an ATP-powered drug efflux pump, remains
one of the most studied membrane transporters. Pgp genes from human, mouse, and
Chinese hamster, among others, have been cloned and sequenced, and homologs have
been identified in other species, including
Drosophila melanogaster
and
Caenorhab-
ditis elegans
.
1
,
2
Pgp in higher mammals forms a small gene family, with two iso-
forms expressed in humans and three isoforms in rodents. The class I and III isoforms
(human
MDR1/ABCB1
, mouse
mdr1/Abcb1a
and
mdr3/Abcb1
) are drug transporters,
while the class II isoforms (human
MDR2/3/ABCB4
, mouse
mdr2/Abcb4
) carry out
export of phosphatidylcholine (PC) into the bile.
3
The two human genes arose from
a duplication event and are adjacent to each other on the chromosome. The drug-
transporting isoform shares 78% amino acid sequence identity with the PC-exporting
isoform, suggesting that they share similar structures and mechanisms of action. For
the rest of this chapter, the term
Pgp
is used to indicate the ABCB1 gene product.
10.2. TISSUE DISTRIBUTION OF P-GLYCOPROTEIN
Early studies of Pgp distribution in human
4
and rodent
5
tissues showed that the protein
is expressed at low levels in most tissues but is found in much higher amounts at the
apical surface of epithelial cells lining the colon, small intestine, pancreatic ductules,
bile ductules and kidney proximal tubules, and the adrenal gland. Thus, epithelial
cells with excretory roles generally express Pgp. The transporter is also located in the
endothelial cells of the blood-brain barrier,
6
the blood-testis barrier,
7
and the blood-
mammary tissue barrier,
8
and has recently been found to play a role in the blood-inner
ear barrier, where it is expressed in the capillary endothelial cells of the cochlea and
vestibule.
9
Thus the role of Pgp in the blood-brain and blood-tissue barriers is likely to
protect these organs from toxic compounds that gain entry into the circulatory system.
Pgp is expressed at high levels at the luminal surface of secretory epithelial cells in the
pregnant endometrium,
10
as well as the placenta,
11
where it may provide protection
for the fetus.
12
The protein is also found on the surface of hematopoietic cells, where
its function remains enigmatic. The ABCB4 protein is expressed at high levels on
the bile canalicular membrane of hepatocytes, in accordance with its proposed role
in transport of PC into the bile.
13
10.3. ROLE OF P-GLYCOPROTEIN IN HUMAN PHYSIOLOGY
The tissue localization of Pgp suggests that the protein plays a physiological role
in the protection of susceptible organs such as the brain, testis, and inner ear from
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