Bilirubin Brain Toxicity

Abstract

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.

RHD maternal–fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order

“…The best-fitting models and the estimated relative risks of RHD MFG incompatibility are consistent with the hypothesized effect of previous incompatible pregnancies on the risk of schizophrenia due to RHD MFG incompatibility, namely that previous incompatible pregnancies increase the risk of Rh incompatibility disease. The hypothesized role of Rh incompatibility disease in schizophrenia risk is consistent with the neurodevelopmental 24 and glial asthenia 13 hypotheses of schizophrenia, as Rh incompatibility disease can lead to fetal hypoxia and an increase in unconjugated bilirubin, 8,9 a neurotoxin than can damage undifferentiated glial cells. 10,11 A previously published analysis of the same set of nuclear families that used only the youngest affected child in each nuclear family reported a one-sided P-value of 0.027.…”

Fasiglifam (TAK-875) Inhibits Hepatobiliary Transporters: A Possible Factor Contributing to Fasiglifam-Induced Liver Injury

“…It was reported that biliary excretion is the rate-limiting step of bilirubin elimination. At high intracellular concentrations, bilirubin can uncouple oxidative phosphorylation, reduce DNA stability, interrupt protein synthesis, and block ATPase activity in brain mitochondria (Hansen, 2001). Therefore, hyperbilirubinemia may provide an early warning of possible adverse effects, such as neurotoxicity and hepatotoxicity.…”

Bilirubin

“…When accumulated at abnormally high concentrations in early life, bilirubin is toxic and is responsible for the clinical symptoms of kernicterus. 12 However, the antioxidant nature of the bile pigments suggests potential beneficial effects as well. 13 Furthermore, there is accumulating evidence from epidemiological studies that individuals with highnormal or just above normal plasma bilirubin levels, including individuals with Gilbert syndrome, have a lesser incidence of coronary heart disease and carotid plaque formation.…”