Modulation of multidrug resistance by flavonoids. Inhibitors of glutathione conjugation and MRP-mediated transport
In this thesis, the use of flavonoids for inhibition of two important players in the glutathione related biotransformation system involved in multidrug resistance was investigated using several in vitro model systems. The enzymes of interest included the phase II glutathione S-transferase enzyme GSTP1-1, able to detoxify anticancer agents through conjugation with glutathione and the two multidrug resistance proteins MRP1 and MRP2 involved in glutathione mediated cellular efflux of, amongst others, anticancer drugs.The studies presented in this thesis reveal that the major site for flavonoid mediated interaction with GSH-dependent multidrug resistance processes are the GS-X pumps MRP1 and MRP2 rather than the conjugating GSTP1-1 activity. Whereas flavonoids are unlikely to be efficient cellular or in vivo GSTP1-1 inhibiting agents useful to reverse this aspect of multidrug resistance, they might be useful as inhibitors of MRP1 and MRP2 activity. A model compound used in this thesis able to inhibit both MRP1 and MRP2 activity, the flavonoid myricetin, was shown to effectively inhibit vincristine efflux by these transporters in MRP1- and MRP2-transfected cells, thereby effectively sensitizing the cells towards the anticancer drug. Moreover, phase II metabolism, occurring to a major extent in vivo , of the other model flavonoid used in this thesis, quercetin, resulted in equally potent or even better inhibitors of MRP1 and MRP2. This indicates that phase II metabolism is unlikely to reduce the MRP inhibiting potential of quercetin for use of this flavonoid as an inhibitor to overcome MRP-mediated multidrug resistance. Furthermore, it was shown that the flavonoid myricetin is unlikely to affect MRP-mediated transport of glutathione conjugates to a significant extent, because, in general, glutathione conjugates such as the glutathione conjugates of the endogenous compound prostaglandin A 2 , are high affinity substrates of MRP1 and MRP2. These results provide an argument for the possible absence of specific negative side effects on the kinetics and physiology of endogenous MRP substrates, to be expected upon use of these natural MRP inhibitors in the reversal of multidrug resistance. Testing of the in vitro outcomes of the present study in clinical settings may start with flavonoids that have already a safe history of use in for example food supplements and requires the confirmation of involvement of the MRPs in specific cases of clinical drug resistance prior to therapeutic use of the flavonoids as MRP inhibitors.
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| Format: | Doctoral thesis biblioteca |
| Language: | English |
| Published: |
Ponsen & Looijen
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| Subjects: | detoxification, drug metabolism, flavonoids, multiple drug resistance, flavonoïden, geneesmiddelmetabolisme, meervoudige resistentie tegen geneesmiddelen, ontgifting, |
| Online Access: | https://research.wur.nl/en/publications/modulation-of-multidrug-resistance-by-flavonoids-inhibitors-of-gl |
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| Summary: | In this thesis, the use of flavonoids for inhibition of two important players in the glutathione related biotransformation system involved in multidrug resistance was investigated using several in vitro model systems. The enzymes of interest included the phase II glutathione S-transferase enzyme GSTP1-1, able to detoxify anticancer agents through conjugation with glutathione and the two multidrug resistance proteins MRP1 and MRP2 involved in glutathione mediated cellular efflux of, amongst others, anticancer drugs.The studies presented in this thesis reveal that the major site for flavonoid mediated interaction with GSH-dependent multidrug resistance processes are the GS-X pumps MRP1 and MRP2 rather than the conjugating GSTP1-1 activity. Whereas flavonoids are unlikely to be efficient cellular or in vivo GSTP1-1 inhibiting agents useful to reverse this aspect of multidrug resistance, they might be useful as inhibitors of MRP1 and MRP2 activity. A model compound used in this thesis able to inhibit both MRP1 and MRP2 activity, the flavonoid myricetin, was shown to effectively inhibit vincristine efflux by these transporters in MRP1- and MRP2-transfected cells, thereby effectively sensitizing the cells towards the anticancer drug. Moreover, phase II metabolism, occurring to a major extent in vivo , of the other model flavonoid used in this thesis, quercetin, resulted in equally potent or even better inhibitors of MRP1 and MRP2. This indicates that phase II metabolism is unlikely to reduce the MRP inhibiting potential of quercetin for use of this flavonoid as an inhibitor to overcome MRP-mediated multidrug resistance. Furthermore, it was shown that the flavonoid myricetin is unlikely to affect MRP-mediated transport of glutathione conjugates to a significant extent, because, in general, glutathione conjugates such as the glutathione conjugates of the endogenous compound prostaglandin A 2 , are high affinity substrates of MRP1 and MRP2. These results provide an argument for the possible absence of specific negative side effects on the kinetics and physiology of endogenous MRP substrates, to be expected upon use of these natural MRP inhibitors in the reversal of multidrug resistance. Testing of the in vitro outcomes of the present study in clinical settings may start with flavonoids that have already a safe history of use in for example food supplements and requires the confirmation of involvement of the MRPs in specific cases of clinical drug resistance prior to therapeutic use of the flavonoids as MRP inhibitors. |
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