Effects of hyperbilirubinaemia on glutathione S-transferase isoenzymes in cerebellar cortex of the Gunn rat

Johnson, Jeffrey A.; Hayward, Jeffrey J.; Kornguth, Steven; Siegel, Frank L.

doi:10.1042/bj2910453

Cited by 14 publications

(11 citation statements)

References 83 publications

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“…The y p (pi‐7) subunit is highly expressed in the CP and cerebellar oligodendrocytes. The y c , y o , and y p subunits are up‐regulated in jaundiced Gunn rats at 20 and 60 days of age [127], too late to ameliorate the cerebellar atrophy that begins in jaundiced Gunn rat pups at approximately 10 days of age [41]. This up‐regulation in GST expression also is smaller and occurs later in the subregions of the cerebellum that exhibit the most kernicterus and hypoplasia [127].…”

Section: Protection Of Cns Cells From High Intracellular Levels Of Ucbmentioning

confidence: 99%

New concepts in bilirubin encephalopathy

Ostrow¹,

Pascolo²,

Shapiro³

et al. 2003

Eur J Clin Investigation

138

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Revised concepts of bilirubin encephalopathy have been revealed by studies of bilirubin toxicity in cultured CNS cells and in congenitally jaundiced Gunn rats. Bilirubin neurotoxicity is related to the unbound (free) fraction of unconjugated bilirubin (B f ), of which the dominant species at physiological pH is the protonated diacid, which can passively diffuse across cell membranes. As the binding affinity of plasma albumin for bilirubin decreases strikingly as albumin concentration increases, previously reported B f values were underestimated. Newer diagnostic tests can detect reversible neurotoxicity before permanent damage occurs from precipitation of bilirubin (kernicterus). Early toxicity can occur at B f only modestly above aqueous saturation and affects astrocytes and neurons, causing mitochondrial damage, resulting in impaired energy metabolism and apoptosis, plus cell-membrane perturbation, which causes enzyme leakage and hampers transport of neurotransmitters.The concentrations of unbound bilirubin in the cerebro-spinal fluid and CNS cells are probably limited mainly by active export of bilirubin back into plasma, mediated by ABC transporters present in the brain capillary endothelium and choroid plexus epithelium. Intracellular bilirubin levels may be diminished also by oxidation, conjugation and binding to cytosolic proteins.These new concepts may explain the varied susceptibility of neonates to develop encephalopathy at any given plasma bilirubin level and the selective distribution of CNS lesions in bilirubin encephalopathy. They also can suggest better strategies for predicting, preventing and treating this syndrome.Keywords Bilirubin, jaundice, neonates, nuerotoxicity, encephalopathy, kernicterus. Abbreviations: BE, bilirubin encephalopathy; UCB, unconjugated bilirubin; BAEP, brainstem auditory evoked potentials; B f , free (unbound) fraction of UCB; HSA, human serum albumin; K f , affinity constant for binding of UCB to albumin; CSF, cerebrospinal fluid; BBB, blood-brain barrier; CP, choroid plexus. Eur J Clin Invest 2003; 33 ( 11): 988 -997

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Section: Protection Of Cns Cells From High Intracellular Levels Of Ucbmentioning

confidence: 99%

New concepts in bilirubin encephalopathy

Ostrow¹,

Pascolo²,

Shapiro³

et al. 2003

Eur J Clin Investigation

138

View full text Add to dashboard Cite

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“…from hydrogen peroxide) can cross the blood-brain barrier and induce increased expression of gst isoenzymes in the CNS. [126]. The same might be true of UCB derivatives or by-products of UCB oxidation.…”

Section: Potential Modulation Of Bilirubin Neurotoxicty By Mdr1/mdr1 mentioning

confidence: 91%

The molecular basis of bilirubin encephalopathy and toxicity: Report of an EASL Single Topic Conference, Trieste, Italy, 1–2 October, 2004

Tiribelli

Ostrow

2005

Journal of Hepatology

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“…As mentioned briefly above, bilirubin binds to brain glutathione S-transferase, which is enriched in the cytosol, and to some extent in microsomes and mitochondria (28). Cytosolic glutathione S-transferases in rat brain are increased in hyperbilirubinemia, and the regional pattern of distribution is altered (29). Battiston et al (30) recently detected two peptides in rat brain (79 and 34 kD) that bound bilirubin.…”

Section: Discussionmentioning

confidence: 99%

Subcellular Localization of Bilirubin in Rat Brain after In Vivo i.v. Administration of [3H]Bilirubin

2001

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Bilirubin appears to be toxic in vitro to several cellular functions localized to different subcellular compartments. It would therefore be useful to know what concentrations of bilirubin might be found in cell organelles in vivo. Rats were anesthetized and allocated to one of three groups: control, hypercarbia, and hyperosmolality. Each rat received a 5-min bolus dose of bilirubin 50 mg/kg i.v. (containing approximately 200 Ci [ 3 H]bilirubin). Rats were killed 10 or 30 min after the start of the bilirubin infusion. Each brain was homogenized, and subcellular fractions were isolated by high-speed gradient centrifugation in sucrose media. The gradients were separated into aliquots of 2 mL, and the protein content was determined in each aliquot. Radioactivity was determined by scintillation counting, and the content of bilirubin per milligram of protein was calculated. Statistical comparisons were performed with KruskalWallis nonparametric ANOVA. There were highly significant differences in bilirubin content per milligram of protein among subcellular compartments in all groups and at both time points. In all groups there were relatively high concentrations of bilirubin in the myelin fraction, an interesting observation in light of the theory that membranes are the primary target of bilirubin toxicity. The very high concentration of bilirubin relative to protein in cytoplasm, ribosomes, and mitochondria in the hyperosmolar group are also notable in light of data from hyperbilirubinemic animals in which changes in electrophysiology or energy metabolism only appeared after hyperosmolar opening of the bloodbrain barrier. The present data may be useful in planning in vitro studies of bilirubin toxicity in cell organelles. Abbreviations: P1, P2, P3, P4, first, second, third, and fourth pellets from sequential density centrifugations S1, S2, S3, S4, first, second, third, and fourth supernatants from sequential density centrifugations Neonatal jaundice is a common and, in most infants, normal physiologic event, which has been discussed in the medical literature for at least a quarter of a millennium (1). Some jaundiced infants exhibit signs of neurotoxicity, which appears to be transitory in the great majority. Exceptionally, bilirubin toxicity may result in death in the newborn period or in survival with severe neurologic sequelae (kernicterus). During the past 50 y considerable research effort has been directed toward the interaction between bilirubin and the brain, as well as the mechanism (or mechanisms) of neurotoxicity.Much has been learned about how bilirubin enters into and is cleared from the brain, but the process that leads to deposition of bilirubin in basal ganglia and other brain regions to create the pattern known as kernicterus (jaundice of the nuclei) is as yet not understood. Also, none of the theories concerning the basic neurobiological mechanism of bilirubin neurotoxicity have been conclusively proven.A number of methodological problems have bedeviled bilirubin researchers and impeded progress. One o...

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Effects of hyperbilirubinaemia on glutathione S-transferase isoenzymes in cerebellar cortex of the Gunn rat

Cited by 14 publications

References 83 publications

New concepts in bilirubin encephalopathy

New concepts in bilirubin encephalopathy

The molecular basis of bilirubin encephalopathy and toxicity: Report of an EASL Single Topic Conference, Trieste, Italy, 1–2 October, 2004

Subcellular Localization of Bilirubin in Rat Brain after In Vivo i.v. Administration of [3H]Bilirubin

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