Inhibition of multidrug resistance proteins MRP1 and MRP2 by a series of α,β-unsaturated carbonyl compounds

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…The last notable type of processes that contributes to the low systemic bioavailability of curcumin and/or the generation of curcumin metabolites entails the association of curcumin with intestinal nondetoxification proteins. In some instances the binding of curcumin to a protein relays an inhibitory effect, as has been shown for several ATP-binding cassette (ABC) transporters (Wortelboer et al, 2003(Wortelboer et al, , 2005Shukla et al, 2009) and CYP isozymes (Volak et al, 2008), whereas in other instances the binding can be both antagonistic and biotransformative, as is the case for, e.g., SULTs (Eaton et al, 1996;Ireson et al, 2002;Volak et al, 2008;Fong et al, 2012), UGTs (Volak et al, 2008;Berginc et al, 2012;Dempe et al, 2012;Fong et al, 2012), and GSTs (Awasthi et al, 2000). With respect to nondetoxifying enzymes, the combined antagonistic and catalytic effects have been demonstrated for curcumin-COX-2 (Hong et al, 2004;Selvam et al, 2005;Griesser et al, 2011) and curcumin-lipoxygenase complexes (Skrzypczak-Jankun et al, 2000;Toth et al, 2000;Hong et al, 2004;Prasad et al, 2004), which result in the formation of 6-hydroxy-1-(4-hydroxy-3-methoxyphenoxy)-3-(4-hydroxy-3-methoxyphenyl)-1,3,3a,6a-tetrahydro-4H-cyclopenta[c]furan-4-one (Fig.…”

“…Several studies have demonstrated that curcumin is capable of inhibiting various ABC transporters (Wortelboer et al, 2003(Wortelboer et al, , 2005Shukla et al, 2009), which is likely to affect the transport kinetics of curcumin and its metabolites in, e.g., enterocytes and hepatocytes, because these cells are replete with multiple ABC transporters (section III.C.2.f). Cancer cells also overexpress multiple ABC transporters (Brozik et al, 2011) that confer multidrug resistance (Tiwari et al, 2011).…”

Biliary Excretion of Curcumin Is Mediated by Multidrug Resistance-Associated Protein 2

“…Although there are no data examining whether curcumin is a substrate of Mrp2, curcumin is known to interact with Mrp2 as an inhibitor. 18,19) Thus, we hypothesized that Mrp2 could be involved in the hepatobiliary excretion of curcumin.…”

Metabolism of ATP-binding cassette drug transporter inhibitors: complicating factor for multidrug resistance

“…For another αβ-unsaturated carbonyl compound, caffeic acid phenethyl ester, no inhibition of MRP1 and MRP2 was observed when tested in the Sf9 vesicle model, whereas in intact transfected MDCKII cells a clear inhibition of transport by these compounds was observed, indicating that possibly a metabolite could be responsible for the MRP1 and MRP2 inhibition [130]. Comparable studies have been performed for other compounds that react with GSH and/or GST, such as thiotepa [34], ethacrynic acid [131,132], prostaglandins [132][133][134][135] and αβ-unsaturated aldehydes [115,130,132].…”

“…Comparable studies have been performed for other compounds that react with GSH and/or GST, such as thiotepa [34], ethacrynic acid [131,132], prostaglandins [132][133][134][135] and αβ-unsaturated aldehydes [115,130,132]. This complex interplay between MRP inhibition and metabolism of MRP inhibitors, the latter affecting the ultimate potential of a compound for cellular MRP inhibition, may exist not only for these GSH-reactive compounds, but also for many other MRP inhibitors presently or previously developed on the basis of especially vesicle studies.…”