Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 285, Issue 6, Pages G1335-G1344Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00271.2003
Keywords
glutathione conjugates; glutathione-chelerythrine adduct; membrane transport; membrane vesicles; polarized cells
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Funding
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK048522, R01DK030312] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG007467] Funding Source: NIH RePORTER
- NIA NIH HHS [R01-AG-7467] Funding Source: Medline
- NIDDK NIH HHS [R01-DK-30312, P30-DK-48522] Funding Source: Medline
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Rat multidrug resistant protein 2 (Mrp2; Abcc2), an ATP-driven pump located on the canalicular domain of hepatocytes, exports glutathione S-conjugates (GS-X) and GSH among its wide variety of substrates. Previous studies have shown that chelerythrine (CHEL), a quaternary benzophenanthridine cation, reacts with GSH to form a reversible adduct under physiological conditions. Here we report that CHEL can strongly stimulate GSH efflux by Mrp2, when it is constitutively expressed in polarized canine kidney cells, thereby leading to the depletion of cellular GSH. Transepithelial transport experiments indicate that Mrp2 transports GSH and CHEL with a 1:1 stoichiometry, which can be readily inhibited by GS-bimane, a GS-X substrate for Mrp2. Moreover, CHEL can block Mrp2-mediated leukotriene C-4 uptake by membrane vesicles with an IC(50)approximate to100 muM in the presence of GSH, but not S-methyl GSH or ophthalmic acid. Thus the thiol group of GSH is required for inhibition of Mrp2 in the presence of CHEL. Our results suggest that CHEL stimulates GSH efflux by forming a reversible GS-CHEL adduct, which is transported by Mrp2 and dissociates extracellularly.
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