Biomedical Engineering Reference
In-Depth Information
MRP1 is able to cotransport neutral/basic drugs with reduced GSH: In in vitro exper-
iments it has been reported that the ATP-dependent vesicular transport of vincristine,
daunorubicin, and etoposide by MRP1 required reduced GSH, and GSH-depleting
agents such as buthionine sulfoximine (BSO) could sensitize MRP1-overexpressing
cells to a number of anticancer agents.
292
,
297
-
303
Antimonial and arsenical oxian-
ions are also cotransported by MRP1 with GSH
304
or complexed to GSH.
303
Thus,
MRP1 transports a broad range of physiological compounds, xenobiotics, and drugs.
Leukotriene C
4
(LTC
4
) and its metabolites, D
4
(LTD
4
) and E
4
(LTE
4
), are good
substrates of MRP1, as well as other prostaglandin derivatives, the cholestatic 17
-
estradiol-glucuronide and the sulfated bile salt sulfatolithocholate.
290
,
292
,
295
,
305
A vari-
ety of chemical toxicants and their metabolites with potential carcinogenic activity are
also transported by MRP1. In vitro data show that the GSH-conjugated stereoisomers
of aflatoxin B1,
306
the glucuronide conjugate of some nicotine metabolites,
296
,
307
the GSH conjugates of the herbicide metolachlor, and the toxicants 1-Cl-2,4-
dinitrobenzene and 4-nitroquinoline 1-oxide are all substrates of MRP1.
308
-
310
Clin-
ically relevant substrates of MRP1 include several classes of anticancer agents, such
as anthracenedione (mitoxantrone); epipodophyllotoxins;
Vinca
alkaloids; anthracy-
clines; camptothecins (topotecan, irinotecan, and the unconjugated and conjugated
forms of its active metabolite SN-38)
311
; conjugates of alkylating agents (thiotepa,
312
cyclophosphamide, chlorambucil, and melphalan); and the antiandrogen flutamide
and its metabolite, hydroxyflutamide.
313
MRP1 can also confer resistance to short-
term exposure to methotrexate, a folate antimetabolite.
244
,
248
Recently, the HIV
protease inhibitors ritonavir and saquinavir, as well as conjugates of the diuretic
ethacrynic acid,
316
were found to be transported by MRP.
314
,
315
Inhibitors (Competitive and Noncompetitive)
Various classes of compounds with
MRP-inhibiting activity have been described. Sulfinpyrazone, benzbromarone,
probenecid, and indomethacin can modulate MRP1 activity, but they are nonspecific
inhibitors, as these molecules modulate the activity of many transporters, and based on
in vitro findings, they should be used at relatively high concentrations to inhibit MRP1
activity in vivo.
317
-
320
Relatively specific modulators of MRP1 are MK571 (a LTD
4
receptor antagonist),
321
ONO-1078 (a peptide leukotriene receptor antagonist),
322
glibenclamide [a sulfonylurea derivative that inhibits MRP1 as well as sulfony-
lurea receptor 1 (SUR1)]
323
and several peptidomimetic GSH-conjugate analogs.
324
Several tricyclic isoxazole derivatives (e.g., LY475776, LY329146, LY402913) are
highly specific and potent MRP1 inhibitors, as they block the MRP1-mediated
LT C
4
transport in a GSH-dependent manner.
294
,
325
-
327
Some Pgp inhibitors, such
as VX-710 (Biricodar), PSC 833 (valspodar), verapamil,
328
cyclosporin A, agosterol
A,
329
PAK-105P,
330
,
331
S9788
332
as well as several bioflavonoids (e.g., genistein,
quercetin),
333
,
334
nonsteroidal anti-inflammatory drugs (NSAIDs),
335
steroid deriva-
tives (e.g., RU486, budesonide), and imidathiazole derivatives have been shown
to inhibit MRP1, but with low affinity and poor specificity.
296
Recently, MRP1-
specific antisense oligonucleotides and cDNA, ribozymes, and small interfering RNA
molecules have been developed. For instance, ISIS 7597 (a MRP1-specific antisense
Search WWH ::
Custom Search