Bilirubin brain toxicity.
Bilirubin is toxic in most biological systems tested. Several mechanisms have been suggested for this toxic effect, including inhibition of enzyme systems and inhibition of cell regulatory reactions (protein/peptide phosphorylation). The identity of the basic mechanism(s) has not been conclusively proven, but inhibition of peptide phosphorylation, perhaps mediated or modulated by lysine at the active site(s), appears to be compatible with many of the observations currently found in the literature. Bilirubin entry into brain is facilitated by drug displacement of bilirubin from its albumin binding, reduced albumin binding capacity, increased brain bloodflow, increased permeability of the blood-brain barrier, and other factors. The rate of bilirubin entry into brain, as well as the degree of retention and rate of clearance from brain, depends on which of these circumstances are operative. It is as yet unclear whether the mechanism responsible for increased brain bilirubin is important for toxicity. The mechanism for preferential localization of bilirubin to the basal ganglia in kernicterus is also not known. Bilirubin appears to distribute differentially to brain subcellular compartments and is oxidized in brain by an enzyme localized on the inner mitochondrial membrane. This enzyme is found both in neurons and in glia, but appears to be more active in the latter. The activity increases with postnatal age, and is subject to genetic variability in animals. The enzyme is cytochrome c-dependent. It is as yet not clear whether the activity of this enzyme serves a brain-protective effect in severe hyperbilirubinemia.
Hansen
T W
TW
Section on Neonatology, Department of Pediatrics, Rikshospitalet, Oslo NO-0027, Norway.
D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism / Q000633:toxicity*; D001921:Brain / Q000378:metabolism*; D006461:Hemolysis; D006801:Humans; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000378:metabolism; D007647:Kernicterus / Q000378:metabolism; D010084:Oxidation-Reduction
D001663:Bilirubin