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.

Keywords: ABC transporters; OATP; UDP-glucuronosyltransferase; astrocyte; biliverdin; blood–brain barrier; choroid plexus; glutathione-S-transferase.

Figure 1

Cellular effectors involved in the bioavailability and toxicity of UCB. Bilirubin exchanges between blood and brain occur mainly across the microvessel walls forming the blood–brain barrier (BBB) or the choroid plexus epithelium forming the blood–cerebrospinal fluid barrier (BCSFB). The cells forming these barriers are sealed by tight junctions (black dots and lines). The fenestrated choroidal vessels allow extensive exchanges between the blood and the choroidal stroma. CSF–brain exchanges take place across the ependyma, or the pia–glia limitans (not shown here). Within the neuropil, neurons are the terminal target of bilirubin toxicity. Astrocytes, microglia, and oligodendrocytes all play a role in controlling bilirubin toxicity-over-benefit balance.