Biomedical Engineering Reference
In-Depth Information
of these proteins has a protective effect that has been widely conserved throughout
evolution.
The majority of multidrug resistance transporter research has focused on
P-glycoprotein (Pgp), a xenobiotic efflux transporter that is encoded by
ABCB1
.
Pgp was identified in 1979 as the protein that reduced the permeability of Chinese
hamster ovary (CHO) cells, thereby limiting the intracellular accumulation of the
anti-inflammatory drug colchicine.
120
In the 1980s, Pgp was found to cause resis-
tance to a wide spectrum of drugs, including anticancer agents, and overexpression
of the transporter in tumor samples and cell lines was reported.
121
Characterization
of the substrate specificity and elucidation of the molecular mechanism of Pgp has
progressed, but many aspects of this transporter remain to be investigated.
A number of associations with SNPs in ABC transporters and various pharmacoki-
netic or pharmacodynamic phenotypes have been reported in the last five years. The
genotype-phenotype approach was commonly used to study the effects of
ABCB1
polymorphisms and response to drug therapy. The coding region of the gene was first
sequenced in 2000 in a small number of healthy subjects in whom Pgp expression
and function had also been characterized. A number of polymorphisms were found,
one of which, the synonymous 3435C
T SNP, was associated with decreased in-
testinal Pgp function and expression.
8
More comprehensive SNP discovery efforts
followed, in larger cohorts and in ethnically diverse populations.
9
,
10
,
122
Those SNPs
that occurred at high frequencies or which were predicted to have a functional ef-
fect were examined in vitro. The most widely studied SNPs included 3435C
>
>
T,
2677G
T, which were found to be in signifi-
cant linkage disequilibrium.
9
,
10
,
123
The common haplotype containing 3435T, 2677T
(893Ser), and 1236T was named
ABCB1
*13 and had a frequency greater than 30%
in Caucasians, Asian Americans, Mexican Americans, and Pacific Islanders.
10
The in vitro analyses of the functional consequences of some of these SNPs were
suggestive of a clinical effect; for example, one study reported a significant increase
in digoxin efflux associated with the
ABCB1
*13 haplotype, although protein expres-
sion was not influenced.
9
Clinical pharmacogenetics studies quickly followed, with
results that were often conflicting. Complicating the matter was the fact that most
studies looked at each SNP individually instead of considering them in their naturally
occurring haplotypes. For instance, several studies found that the 3435T genotype in-
creased digoxin AUC significantly but found no significant correlation between 2677
genotype and digoxin pharmacokinetics.
124
,
125
Another study found no association
between 3435 genotype and digoxin pharmacokinetics.
126
It is probable that multiple
haplotypes were included in each genotype group, and for this reason, the effects of
these haplotypes may have been obscured.
While there are many reports on
ABCB1
polymorphisms and pharmacokinet-
ics of clinically used Pgp substrates, including digoxin,
127
fexofenadine,
128
and
cyclosporine,
129
there are also a number of studies that examine the effects of
ABCB1
polymorphisms on clinical endpoints such as drug response or survival. The predic-
tive value of
ABCB1
genotype has been studied with respect to rates of remission
and survival in patients with acute myeloid leukemia (AML). One study found that
the wild-type 1236C, 2677G, and 3435C alleles were associated with significantly
>
A/T (Ala893Ser/Thr), and 1236C
>
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