Biomedical Engineering Reference
In-Depth Information
ABCC3-expressing cells.
48
,
112
The resistance to methotrexate was further charac-
terized using membrane vesicles demonstrating ABCC3-mediated ATP-dependent
transport of folate, methotrexate, and
N
5
-formyltetrahydrofolate (leucovorin), but not
of the polyglutamylated metabolites of methotrexate.
113
Unlike ABCC1 and ABCC2,
ABCC3 does not mediate significant resistance to
Vinca
alkaloids, doxorubicin, cis-
platin, and paclitaxel.
112
,
148
11.4.4. ABCC4
Functional characterization identified ABCC4 as an ATP-dependent organic anion
transporter of broad substrate specificity. The first substrates of ABCC4 identified
were nucleoside monophosphate analogs that act as inhibitors of HIV reverse tran-
scriptase and are used as antiretroviral drugs.
114
The human T-lymphoid cell line CEM,
selected for resistance to nucleoside monophosphate analogs, showed amplification of
the
ABCC4
gene and increased ABCC4 expression associated with increased efflux of
9-(2-phosphonylmethoxyethyl)adenine (PMEA, a nucleoside phosphonate analog),
azidothymidine (AZT) monophosphate, as well as other nucleoside monophosphate
analogs.
114
These results were confirmed with cells expressing recombinant ABCC4.
These cells, additionally, showed increased resistance to purine analogs such as
6-thioguanine and 6-mercaptopurine, as well as to the antiviral agent ganciclovir, used
in chemo- and immunotherapy.
50
,
115
−
117
However, the multidrug resistance profile of
ABCC4 does not include natural-product drugs such as anthracyclines, etoposide,
Vinca
alkaloids, and paclitaxel.
115
Several studies demonstrated that ABCC4 mediates transport of the cyclic nucleo-
tides guanosine 3
,5
-monophosphate (cGMP) and adenosine 3
,5
-monophosphate
(cAMP).
50
,
51
,
116
Lai and Tan proposed that ABCC4-mediated transport of cyclic nu-
cleotides is influenced by GSH.
50
Inhibition of GSH synthesis resulted in a decreased
efflux of cAMP from the cells, even when synthesis of cAMP was stimulated with
forskolin.
50
However, no direct demonstration of this stimulation has been reported
in inside-out membrane vesicles. In addition to the cyclic nucleotides, ABCC4 also
regulates ADP storage in dense granules from human platelets.
118
In platelet mem-
brane vesicles, ABCC4-mediated transport of ADP was orthovanadate-sensitive, and
transport of cGMP and cAMP was ATP-dependent.
118
Transport of the physiological substrate folate and its antimetabolites methotrexate
and methotrexate polyglutamate was also detected in ABCC4-transfected cells.
51
,
119
ABCC4 is also an efflux pump for the endogenous conjugates E
2
17
G
51
,
116
and DHEAS.
120
Furthermore, ABCC4 mediates ATP-dependent transport of the
prostaglandins PGE
1
and PGE
2
.
121
Indirect evidence based on inhibition of PGE
2
transport suggested that other prostanoids may be substrates as well.
121
Independent
studies demonstrated that ABCC4 mediates transport not only of PGE
2
but also of
PGF
2
α
and thromboxane B
2
.
122
Thus, ABCC4 can be considered as an export pump
for prostanoids.
122
Nonsteroidal anti-inflammatory drugs inhibited ABCC4-mediated
E
2
17
β
G transport.
121
At present, direct evidence of GSH transport by ABCC4 has been reported only by
our group.
53
,
123
In vesicles from ABCC4-expressing V79 hamster fibroblasts, ATP-
dependent transport of monoanionic bile salts was detected only in the presence of
β
Search WWH ::
Custom Search