Transport and Metabolism at Blood–Brain Interfaces and in Neural Cells: Relevance to Bilirubin-Induced Encephalopathy

Abstract

Bilirubin, the end-product of heme catabolism, circulates in non-pathological plasma mostly as a protein-bound species. When bilirubin concentration builds up, the free fraction of the molecule increases. Unbound bilirubin then diffuses across blood–brain interfaces (BBIs) into the brain, where it accumulates and exerts neurotoxic effects. In this classical view of bilirubin neurotoxicity, BBIs act merely as structural barriers impeding the penetration of the pigment-bound carrier protein, and neural cells are considered as passive targets of its toxicity. Yet, the role of BBIs in the occurrence of bilirubin encephalopathy appears more complex than being simple barriers to the diffusion of bilirubin, and neural cells such as astrocytes and neurons can play an active role in controlling the balance between the neuroprotective and neurotoxic effects of bilirubin. This article reviews the emerging in vivo and in vitro data showing that transport and metabolic detoxification mechanisms at the blood–brain and blood–cerebrospinal fluid barriers may modulate bilirubin flux across both cellular interfaces, and that these protective functions can be affected in chronic unconjugated hyperbilirubinemia. Then the in vivo and in vitro arguments in favor of the physiological antioxidant function of intracerebral bilirubin are presented, as well as the potential role of transporters such as ABCC1 and metabolizing enzymes such as cytochromes P-450 in setting the cerebral cell- and structure-specific toxicity of bilirubin following hyperbilirubinemia. The relevance of these data to the pathophysiology of bilirubin-induced neurological diseases is discussed.

Developmental changes in the transcriptome of the rat choroid plexus in relation to neuroprotection

“…The Ugt1a1 isoform plays an important physiological role in the hepatic clearance of bilirubin in addition to xenobiotics. Conjugation of bilirubin at the blood-CSF barrier could represent an efficient mechanism to prevent the cerebral accumulation of bilirubin in hyperbilirubinemia [77]. …”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…These compounds include various environmental pollutants and drugs from diverse therapeutical classes (anti-tumoral, anti-epileptic, anti-infectious, anti-depressant, immunosuppressant 1 3 (reviewed in [149]). The transporter ABCC1 may also restrict the penetration of plasma unconjugated bilirubin into CSF [45], and thus contribute to protect the brain in case of moderate transient hyperbilirubinemia, such as occurring in neonatal jaundice. The expression in the choroidal epithelium of ABCB1 and ABCG2, two hallmark transporters of the BBB, is debated [44,91,119].…”

“…They also clear intracellularly produced metabolites formed by the panel of detoxifying conjugating enzymes UDP-glucuronosyltransferases (UGT), glutathione-S-transferases (GST), and sulfotransferases (ST). Further protection is provided by antioxidant enzymes (catalase, superoxide dismutase SOD, glutathione peroxidases GPx) and by epoxide hydrolase, which inactivate reactive oxygen species and reactive pro-oxidant epoxides, respectively ◂ depresses ABCC1 levels, which may actually potentiate bilirubin neurotoxicity [45]. Of importance, cytoprotective transporters and enzymes are under the transcriptional regulation of nuclear factors, which are expressed in the choroid plexuses [73].…”

Molecularly Imprinted Quartz Crystal Microbalance Sensor (QCM) for Bilirubin Detection

“…Unconjugated bilirubin (UCB) can behave as an antioxidant agent at low concentrations and provide a positive health effect on hyperbilirubinemia (in case of the increase of UCB in the blood) patients [3,4]. High concentrations of UCB accumulate in many tissues, especially in the brain, due to its lipophilic nature, so it cannot be excreted [5].…”