Biomedical Engineering Reference
In-Depth Information
11.4.8. ABCC11 and ABCC12
Initial studies on ABCC11 proposed this transporter as a cyclic nucleotide efflux
pump.
131
Intact LLC-PK
1
cells expressing recombinant human ABCC11 showed
enhanced cellular efflux of cAMP after stimulation of the intracellular cAMP syn-
thesis by forskolin, an activator of adenylate cyclase.
131
Similar results were ob-
served for the efflux of cGMP. These results were confirmed by transport studies in
inside-out membrane vesicles in a subsequent study, in which the substrate speci-
ficity of ABCC11 was analyzed extensively.
132
In addition to cAMP and cGMP,
ABCC11 is able to transport LTC
4
and DNP-SG, E
2
17
β
G, the monoanionic bile
salts cholylglycine and cholyltaurine, folate and its antimetabolite methotrexate, and
the steroid sulfates E
1
3S and DHEAS.
132
The steroid transport was restricted to the
sulfoconjugates, whereas unconjugated steroids were not transported. The ABCC11-
mediated transport of E
1
3S and DHEAS was further confirmed in vesicles from
MDCK cells expressing recombinant ABCC11.
60
G was stimu-
lated by DHEAS, but transport of DHEAS was not stimulated by E
2
17
Transport of E
2
17
β
G, suggest-
ing a nonreciprocal interaction of both substances.
132
Several compounds were able
to inhibit ABCC11-mediated DHEAS transport, including some well-known CFTR
inhibitors, such as the arylaminobenzoates diphenylamine-2-carboxylate and 5-nitro-
2-(3-phenylpropylamino)benzoate.
60
The ABCC11-transfected LLC-PK
1
cells were
resistant to a variety of nucleoside and nucleotide analogs, including the fluoropy-
rimidines 5-fluorouracil, 5-fluoro-2
-deoxyuridine, and 5-fluoro-5
-deoxyuridine, as
well as 2
,3
-dideoxycytidine and PMEA.
131
ATP-dependent transport of 5-fluoro-
2
-deoxyuridine monophosphate was detected in ABCC11-expressing cells; in con-
trast, no transport of 5-fluorouracil or 5-fluoro-2
-deoxyuridine was detected.
131
For
ABCC12, no functional characterization and no multidrug resistance profile have
been reported so far.
β
11.5. LOCALIZATION OF ABCC/MRP EFFLUX PUMPS IN NORMAL
HUMAN TISSUES AND IN HUMAN CANCERS
By screening the human EST databases (“Unigene” database at http://www.ncbi.
nlm.nih.gov) one can assess the mRNA expression profile of each ABCC/MRP efflux
pump. Whereas
ABCC1, ABCC3, ABCC4, ABCC5,
and
ABCC10
transcripts are found
in almost all of the 46 tissues analyzed,
ABCC2
and
ABCC6
mRNA expression is
restricted to about 12 and that of
ABCC11
and
ABCC12
to seven and five of the
investigated tissues, respectively. Because the protein levels need not be proportional
to the levels of the corresponding mRNAs, it is essential to analyze the ABCC/MRP
protein expression profiles as well. Moreover, ABCC/MRP protein expression is
often cell-type specific, and localization of the transporters in distinct cell types of a
given tissue is therefore equally important. Protein expression and localization studies
in normal human tissues and in human cancers have been performed primarily for
ABCC1 to ABCC6 (Sections 11.5.1 to 11.5.6). Increasing knowledge of the function
and localization will advance the understanding of ABCC/MRP-mediated substance
transport in various tissues.
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