Biomedical Engineering Reference
In-Depth Information
Interactions with MRPs
A growing number of reports have been published regard-
ing the modulating effects of flavonoids on MRPs. Many flavonoids have been shown
to interact with MRPs, and the potential mechanisms of MRPs reversal might involve
(1) decreasing intracellular glutathione (GSH) concentrations via stimulating GSH
transport, (2) altering the expression of MRPs, (3) influencing drug transport pos-
sibly via direct or indirect binding interactions with MRPs at substrate or allosteric
binding sites, and (4) affecting ATPase activity, ATP binding, and ADP release (Table
22.4). Using recombinant nucleotide-binding domain (NBD1) from human MRP1,
Trompier et al.
160
studied the direct interactions of flavonoids with NBD1 and re-
vealed the presence of multiple flavonoid-binding sites. In this study, dehydrosilybin
was found to bind to a ATP-binding site and to inhibit leukotriene C
4
(LTC
4
) transport.
Similar to the case of Pgp, hydrophobic C-isoprenylation of dehydrosilybin increased
the binding affinity for NBD1 but shifted the flavonoid binding outside the ATP site
and decreased the inhibition of LTC
4
transport.
A number of structure-activity relationship studies indicated that flavones and
flavonols were more potent in modulating MRP1 activities than were isoflavones, fla-
vanols, flavanones, and flavanolols. Glycosylation of flavonoids resulted in a decrease
in the inhibitory activity.
146
,
161
,
162
The structural features necessary for high MRP1
inhibitory potency include (1) a planar molecular structure due to the presence of a
2-3 double bond, (2) the presence of both 3
- and 4
-hydroxyl groups on the B ring,
and (3) hydrophobic substitution of 4
-hydroxyl group on the B ring.
161
−
163
In a recent
study including 29 flavonoids, diosmetin (3
,5,7-trihydroxy-4
-methoxyflavone) was
identified as the most potent MRP1 inhibitor, with an IC
50
value of 2.7
M.
162
In contrast to the wide variety of flavonoids that can inhibit MRP1, MRP2 displays
higher selectivity for flavonoid inhibition. Among 29 flavonoids tested, only robinetin
and myricetin inhibited MRP2-mediated calcein efflux, with IC
50
values of 15.0
±
0.6
±
3.5 and 22.2
M, respectively. The presence of a pyrogallol group on the B
ring of flavonols was an important structural characteristic of flavonoids for MRP2
inhibition.
162
±
3.9
Interactions with BCRP
Several recent studies have demonstrated that many natu-
rally occurring flavonoids can inhibit BCRP. Among all the subclasses of flavonoids
tested, flavones seemed to be the most potent BCRP inhibitors
164
,
165
(Table 22.5).
The EC
50
values of the flavones chrysin and apigenin for BCRP inhibition (measured
as the concentration of flavonoids for producing 50% of the maximal increase in mi-
toxantrone accumulation in BCRP-overexpressing MCF-7 MX100 cells) were shown
to be within the sub- or low-micromolar range (0.39
M,
respectively).
165
Glycosylation dramatically decreased the BCRP-inhibiting activi-
ties of some flavonoids.
34
,
164
Recent structure-activity relationship studies indicated
that high BCRP inhibitory potency was associated with flavonoids with the following
characteristics: (1) a planar molecular structure due to the presence of a 2-3 double
bond, (2) hydroxylation at position 5, (3) lack of hydroxylation at position 3; (4) B
ring attached at position 2, and (4) hydrophobic substitution of a 6, 7, 8, or 4
-hydroxyl
group.
165
,
166
Interestingly, it was shown in a recent study that prenylation at position
6 strongly enhanced both inhibitory potency and specificity of flavones. Compared
±
0.13 and 1.66
±
0.55
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