Modulation of human Multidrug Resistance Protein (MRP) 1 (ABCC1) and MRP2 (ABCC2) transport activities by endogenous and exogenous glutathione-conjugated catechol metabolites

Andrew J. Slot, Dana D. Wise, Roger G. Deeley, Terrence Monks, Susan P C Cole

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Members of the multidrug resistance protein (MRP/ABCC) subfamily of ATP-binding cassette proteins transport a wide array of anionic compounds, including sulfate, glucuronide, and glutathione (GSH) conjugates. The present study tested the ATP-dependent vesicular transport of leukotriene C4 and 17β-estradiol 17-(β-D-glucuronide) (E217βG) mediated by the MRP1 and MRP2 transporters in the presence of six potential modulators from three different classes of GSH-conjugated catechol metabolites: the ecstasy metabolite 5-(glutathion-S-yl)-N-methyl-α-methyldopamine (5-GS-N-Me-α-MeDA), the caffeic acid metabolite 2-(glutathion-S-yl)- caffeic acid (2-GS-CA), and four GSH conjugates of 2-hydroxy (OH) and 4-OH estrogens (GS estrogens). MRP1-mediated E217βG transport was inhibited in a competitive manner with a relative order of potency of GS estrogens (IC50 <1 μM) > 2-GS-CA (IC50 3 μM) > 5-GS-N-Me-α-MeDA (IC50 31 μM). MRP2-mediated transport was inhibited with a similar order of potency, except the 2-hydroxy-4- (glutathion-S-yl)-estradiol and 4-hydroxy-2-(glutathion-S-yl)-estradiol conjugates were approximately 50- and 300-fold less potent, respectively. Transport activity was unaffected by N-acetylcysteine conjugates of N-Me-α-MeDA and CA. The position of GSH conjugation appears important as all four GS estrogen conjugates tested were potent inhibitors of MRP1 transport, but only the 2-hydroxy-1-(glutathion-S-yl)-estradiol and 2-hydroxy-1- (glutathion-S-yl)-estrone conjugates were potent inhibitors of MRP2-mediated transport. In conclusion, we have identified three new classes of MRP1 and MRP2 modulators and demonstrated that one of these, the estrogen conjugates, shows unanticipated differences in their interactions with the two transporters.

Original languageEnglish (US)
Pages (from-to)552-560
Number of pages9
JournalDrug Metabolism and Disposition
Volume36
Issue number3
DOIs
StatePublished - Mar 2008

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P-Glycoprotein
Metabolites
Glutathione
Modulation
Estrogens
Estradiol
Inhibitory Concentration 50
P-Glycoproteins
Glucuronides
Modulators
Deoxyepinephrine
Adenosine Triphosphate
Leukotriene C4
catechol
Estrone
Acetylcysteine
Protein Transport
Sulfates
Carrier Proteins
caffeic acid

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Modulation of human Multidrug Resistance Protein (MRP) 1 (ABCC1) and MRP2 (ABCC2) transport activities by endogenous and exogenous glutathione-conjugated catechol metabolites. / Slot, Andrew J.; Wise, Dana D.; Deeley, Roger G.; Monks, Terrence; Cole, Susan P C.

In: Drug Metabolism and Disposition, Vol. 36, No. 3, 03.2008, p. 552-560.

Research output: Contribution to journalArticle

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abstract = "Members of the multidrug resistance protein (MRP/ABCC) subfamily of ATP-binding cassette proteins transport a wide array of anionic compounds, including sulfate, glucuronide, and glutathione (GSH) conjugates. The present study tested the ATP-dependent vesicular transport of leukotriene C4 and 17β-estradiol 17-(β-D-glucuronide) (E217βG) mediated by the MRP1 and MRP2 transporters in the presence of six potential modulators from three different classes of GSH-conjugated catechol metabolites: the ecstasy metabolite 5-(glutathion-S-yl)-N-methyl-α-methyldopamine (5-GS-N-Me-α-MeDA), the caffeic acid metabolite 2-(glutathion-S-yl)- caffeic acid (2-GS-CA), and four GSH conjugates of 2-hydroxy (OH) and 4-OH estrogens (GS estrogens). MRP1-mediated E217βG transport was inhibited in a competitive manner with a relative order of potency of GS estrogens (IC50 <1 μM) > 2-GS-CA (IC50 3 μM) > 5-GS-N-Me-α-MeDA (IC50 31 μM). MRP2-mediated transport was inhibited with a similar order of potency, except the 2-hydroxy-4- (glutathion-S-yl)-estradiol and 4-hydroxy-2-(glutathion-S-yl)-estradiol conjugates were approximately 50- and 300-fold less potent, respectively. Transport activity was unaffected by N-acetylcysteine conjugates of N-Me-α-MeDA and CA. The position of GSH conjugation appears important as all four GS estrogen conjugates tested were potent inhibitors of MRP1 transport, but only the 2-hydroxy-1-(glutathion-S-yl)-estradiol and 2-hydroxy-1- (glutathion-S-yl)-estrone conjugates were potent inhibitors of MRP2-mediated transport. In conclusion, we have identified three new classes of MRP1 and MRP2 modulators and demonstrated that one of these, the estrogen conjugates, shows unanticipated differences in their interactions with the two transporters.",
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AB - Members of the multidrug resistance protein (MRP/ABCC) subfamily of ATP-binding cassette proteins transport a wide array of anionic compounds, including sulfate, glucuronide, and glutathione (GSH) conjugates. The present study tested the ATP-dependent vesicular transport of leukotriene C4 and 17β-estradiol 17-(β-D-glucuronide) (E217βG) mediated by the MRP1 and MRP2 transporters in the presence of six potential modulators from three different classes of GSH-conjugated catechol metabolites: the ecstasy metabolite 5-(glutathion-S-yl)-N-methyl-α-methyldopamine (5-GS-N-Me-α-MeDA), the caffeic acid metabolite 2-(glutathion-S-yl)- caffeic acid (2-GS-CA), and four GSH conjugates of 2-hydroxy (OH) and 4-OH estrogens (GS estrogens). MRP1-mediated E217βG transport was inhibited in a competitive manner with a relative order of potency of GS estrogens (IC50 <1 μM) > 2-GS-CA (IC50 3 μM) > 5-GS-N-Me-α-MeDA (IC50 31 μM). MRP2-mediated transport was inhibited with a similar order of potency, except the 2-hydroxy-4- (glutathion-S-yl)-estradiol and 4-hydroxy-2-(glutathion-S-yl)-estradiol conjugates were approximately 50- and 300-fold less potent, respectively. Transport activity was unaffected by N-acetylcysteine conjugates of N-Me-α-MeDA and CA. The position of GSH conjugation appears important as all four GS estrogen conjugates tested were potent inhibitors of MRP1 transport, but only the 2-hydroxy-1-(glutathion-S-yl)-estradiol and 2-hydroxy-1- (glutathion-S-yl)-estrone conjugates were potent inhibitors of MRP2-mediated transport. In conclusion, we have identified three new classes of MRP1 and MRP2 modulators and demonstrated that one of these, the estrogen conjugates, shows unanticipated differences in their interactions with the two transporters.

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