Biomedical Engineering Reference
In-Depth Information
digoxin and higher plasma drug levels. These results, however, were later contra-
dicted by those of other groups. A recent metaanalysis suggested that the C3435T
SNP has no effect on the expression of MDR1 mRNA or the pharmacokinetics of
digoxin.
211
Conflicting data have been reported on the effects of other alleles using
various drug substrates, and the controversy seems likely to continue. The differ-
ential effects of Pgp polymorphisms on Pgp expression and drug disposition will
probably not be resolved until progress is made in standardizing parameters such as
sample size and makeup, environmental factors, and the assays used for Pgp protein
and mRNA quantification. MDR1 haplotypes, rather than individual SNPs, are also
more likely to affect the pharmacokinetics of MDR1 substrates. Two common Pgp
polymorphisms (G2677T/A and C3435T) may play a role in the differential response
to the cholesterol-lowering statin drugs.
212
When haplotypes were also considered,
a subgroup of female patients was identified who showed a remarkable response to
treatment, which was not linked to a single polymorphism.
Pgp variants carrying spontaneous mutations have been found in cultured cell lines.
The first to be reported was the G195V substitution, which confers increased resis-
tance to colchicine but has little effect on resistance to several other drugs.
213
Deletion
of F335 was reported in another cell line,
214
which also showed altered resistance to
a variety of drugs. The effect of several polymorphic sequence variations common in
human populations on Pgp drug transport function has been investigated in transfected
mammalian cells in vitro. Little difference in cell surface expression and transport
function was noted between any of the variants and the wild-type protein.
215
,
216
On the
other hand, the G1199A polymorphism, which results in a S400N change, changed the
efflux and trans-epithelial flux of a fluorescent substrate, and altered cellular resistance
to some drugs but not to others.
217
Thus, it seems likely that a number of Pgp poly-
morphisms may influence the disposition and therapeutic efficacy of selected drugs.
Given the role played by Pgp in protecting tissues and organs from toxicants, it
would not be surprising to find that polymorphisms play a role in human susceptibility
to various disease states. mdr1 knockout mice spontaneously develop a form of colitis
that can be prevented by antibiotic treatment,
218
suggesting that Pgp functions as a
defense against bacteria or toxins in the intestine. Confirming this idea, inflammatory
bowel diseases (Crohn's disease and ulcerative colitis) are linked to the missense
variant A893S/T,
219
and patients with ulcerative colitis (but not Crohn's disease)
have a higher frequency of the C3435T genotype, which results in lowered Pgp
expression in the intestine.
220
Anti-HIV drugs are known to be Pgp substrates, so a
link between treatment efficacy and Pgp polymorphisms would not be unexpected.
Although several common polymorphisms had no apparent effect on susceptibility to
infection,
221
they were reported to influence drug treatment
222
,
223
; however, this was
contradicted by another study.
224
Variant Pgp alleles can also affect cancer susceptibility. The genotypic frequency
of the C3435T SNP was not altered in colorectal tumor cells from a total patient
population compared to controls
225
; however, when an under-50 patient population
was examined, carriers of the 3435TT genotype or 3435T allele were at substantially
higher risk of developing the disease.
226
Evidence also suggests that Pgp polymor-
phisms influence the risk of developing renal epithelial tumors; C3435T and C3435TT
carriers are again at higher risk.
227
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