Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)
Academic Article
Publication Date:
2004
Short description:
Bilirubin protects astrocytes from its own toxicity by
inducing up-regulation and translocation of multidrug
resistance-associated protein 1 (Mrp1) / Gennuso, Florinda; Fernetti, Cristina; Testa, Nuccio; L'Episcopo, Francesca; Morale, Maria Concetta; Pascolo, Lorella; Tiribelli, Claudio; Tirolo, Cataldo; Caniglia, Salvo; Ostrow, Donald Jay; Marchetti, Bianca Maria. - 101:8(2004), pp. 2470-2475. [10.1073/pnas.0308452100]
abstract:
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 (Bf) 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.Bfabove aqueous saturation produced a similar but aborted
response. Exposure to this higherBffor 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,Bf= 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.
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 (Bf) 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.Bfabove aqueous saturation produced a similar but aborted
response. Exposure to this higherBffor 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,Bf= 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.
Iris type:
1.1 Articolo in rivista
Keywords:
Unconjugated bilirubin (UCB); MRP1; encephalopathy; neonates; neuropharmacology
List of contributors: