Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)

DOI Web Site 被引用文献5件
  • Florinda Gennuso
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • Cristina Fernetti
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • Cataldo Tirolo
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • Nuccio Testa
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • Francesca L'Episcopo
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • Salvo Caniglia
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • Maria Concetta Morale
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • J. Donald Ostrow
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • Lorella Pascolo
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • Claudio Tiribelli
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...
  • Bianca Marchetti
    Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging, 94018 Troina, Italy; Liver Research Center, AREA Science Park and Department of Biochemistry, University of Trieste, 34127 Trieste, Italy; Gastroenterology/Hepatology Division, Department of Medicine, University of Washington School of Medicine and Research Service (151L), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108-1597; and Department of Pharmacology, Faculty of Medicine,...

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<jats:p>Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration (<jats:italic>B</jats:italic><jats:sub>f</jats:sub>)of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma membrane, with a peak 5-fold increase in Mrp1 immunofluorescence intensity from 30 to 120 min.<jats:italic>B</jats:italic><jats:sub>f</jats:sub>above aqueous saturation produced a similar but aborted response. Exposure to this higher<jats:italic>B</jats:italic><jats:sub>f</jats:sub>for 16 h markedly decreased Trypan blue exclusion and methylthiazoletetrazoilum activity and increased apoptosis 5-fold by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay. These toxic effects were modestly increased by inhibition of Mrp1 activity with 3-([3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl-(3-dimethylamino-3-oxopropyl)-thio-methyl]thio)propanoic acid (MK571). By contrast,<jats:italic>B</jats:italic><jats:sub>f</jats:sub>= 40 nM caused injury only if Mrp1 activity was inhibited by MK571, which also blocked translocation of Mrp1. Our conclusion is that in astrocytes, UCB up-regulates expression of Mrp1 and promotes its trafficking from the Golgi to the plasma membrane, thus moderating cytotoxicity from UCB, presumably by limiting its intracellular accumulation.</jats:p>

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