Biomedical Engineering Reference
In-Depth Information
oligonucleotide) has been shown to down-regulate MRP1 successfully in a xenograft
model of human neuroblastoma.
336
Inducers
In some cell systems MRP1 expression can be induced by pro-oxidant
compounds such as quercetin, sulindac, menadione, pyrrolidinedithiocarbamate, and
tert
-butylhydroquinone.
337
-
339
Several compounds that generate reactive oxygen
)
340
and nitric oxide donors
341
are also reported to induce MRP1
species (e.g., TNF
expression.
Pharmacological and Toxicological Function
The pharmacological and toxicolog-
ical functions of MRP1 have been studied using
Mrp1
(
−
/
−
)
mice. Increased sensi-
tivity to the MRP1 substrate etoposide after intravenous administration in
Mrp1
(
−
/
−
)
mice has been described as well as dramatically increased vincristine and etoposide
toxicity after intraperitoneal administration to
Mrp1
(
−
/
−
)
and
Mdr1a/1b
(
−
/
−
)
(triple
knockout) mice compared with
Mdr1a/1b
(
−
/
−
)
and wild-type mice. In particular, the
Mrp1
(
−
/
−
)
and/or
Mdr1a/1b
(
−
/
−
)
mice showed increased sensitivity of bone marrow
precursor cells and some epithelia containing high levels of Mrp1 (e.g., oropharyn-
geal mucosa and collecting tubules of the kidney) to Mrp1 substrate drugs (etoposide
and vincristine). They also showed increased anticancer drug-induced destruction of
sperm cells in the testis and increased drug (etoposide) levels in the cerebrospinal
fluid (CSF).
342
-
346
Recently, MRP1 has been reported to participate in the brain
uptake and accumulation of substrate drugs. Indeed, although saquinavir has been
described as a good Pgp substrate and it has been reported that affinity for Pgp affects
its brain distribution significantly, in a preclinical study in mice the brain uptake of
saquinavir increased more than fourfold in the presence of the selective MRP in-
hibitor MK571.
347
Other in vitro experiments confirmed that at the cellular level, the
endogenous expression of MRP1 (together with Pgp) can contribute to the basal re-
sistance of cell lines to a variety of anticancer drugs. Murine fibroblast and embryonic
stem cell lines lacking the expression of
Mrp1, Mdr1a
, and
Mdr1b
genes displayed
significantly increased sensitivity to anthracyclines, topotecan, SN-38, epipodophyl-
lotoxins, and arsenite.
348
,
349
All these findings together suggest that MRP1 plays an
important role in protection of the body and that administration of MRP1 modulators
can alter the pharmacokinetics of coadministered drugs, thus leading to potentially
clinically relevant drug-drug interactions.
MRP2 (cMOAT, ABCC2)
Impact of Polymorphism on Function
Several mutations of MRP2 (cMOAT,
ABCC2) have been described in humans and animals. In humans some mutations
(missense, nonsense, splice site, and deletion mutations) in the MRP2 gene, resulting
in the absence or functional inactivity of MRP2 in the bile canalicular membrane,
have been reported in persons affected by the Dubin-Johnson syndrome, an auto-
somal recessive inheritable disorder characterized by conjugated hyperbilirubinemia
and increased urinary coproporphyrin I fraction.
15
,
350
Although the hepatic function
of patients with Dubin-Johnson syndrome is reported to be normal (probably due
Search WWH ::
Custom Search