Biomedical Engineering Reference
In-Depth Information
TABLE 11.2. (
Continued
)
Substrate
a
Drug Resistance
b
K
m
(
μ
M)
Refs.
Refs.
S
-Glutathionyl 2,4-dinitrobenzene
132
PMEA
e
131
17
β
-Glucuronosyl estradiol
63
132
17
β
-Glucuronosyl estradiol
+
dehydroepiandrosterone 3-sulfate
c
132
cGMP
e
132
cAMP
e
132
Cholylglycine 132
Cholyltaurine 132
Folate 132
Methotrexate 957 132
a
Compounds listed have been identified as substrates by measurement of the ATP-dependent transport into
inside-out membrane vesicles prepared from ABCC-expressing cells.
b
ABCC-expressing cells confer resistance against the listed compounds by analysis of drug sensitivity.
c
ATP-dependent stimulated transport of the first compound listed by the second compound listed.
d
ATP-dependent cotransport of both compounds; for substrate concentrations, see refs. 53 and 123;
K
m
values refer to the compound not in parentheses.
e
Abbreviations: cAMP, adenosine 3
,5
-cyclic monophosphate; cGMP, guanosine 3
,5
-cyclic monophos-
phate; PMEA, 9-(2-phosphonylmethoxyethyl)adenine.
by ABCC1.
82
,
85
−
88
All these substrates share the property of being organic
amphiphilic anions and conjugates with glutathione, glucuronate, or sulfate. The
glutathione
S
-conjugate LTC
4
is the substrate with the highest affinity for ABCC1
identified so far, with a
K
m
value of 97 nM.
78
As mentioned above, GSSG is a phys-
iological substrate for ABCC1 with a relatively low affinity, suggesting a role of
ABCC1 in the cellular defense against oxidative stress by decreasing concentrations
of GSSG.
83
Moreover, ABCC1 mediates ATP-dependent transport of the cytostatic
drugs vincristine and daunorubicin in the presence of reduced glutathione (GSH),
which functions as a cosubstrate.
89
−
91
GSH itself is not or only poorly transported by
ABCC1
83
,
89
−
91
; however, xenobiotics such as verapamil (a calcium channel blocker
and an inhibitor of MDR1 P-glycoprotein) and several dietary flavonoids, includ-
ing apigenin, stimulate GSH transport without being transported themselves.
92
−
94
In addition, the conjugated estrogen estrone 3-sulfate (E
1
3S) and the tobacco-
specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNAL) were ef-
ficiently transported by ABCC1 only in the presence of GSH, without any evidence
of cotransport.
95
,
96
Thus, GSH can play different roles in the ABCC1-mediated trans-
port: first, as a cosubstrate together with hydrophobic compounds such as the
Vinca
alkaloids vincristine and vinblastine; second, as a substrate, but only in the presence
of xenobiotics such as verapamil and dietary flavonoids; and third, as enhancer of
ABCC1-mediated transport of glucuronated and sulfated conjugates, without being
cotransported itself. These studies suggest that ABCC1 contains a bipartite bind-
ing site for hydrophobic and anionic moieties that allows for binding of conjugated
substrates such as LTC
4
, but allows also for cooperative binding of a hydrophobic
compound and GSH.
89
,
90
,
92
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