Pharmaceutical strategies for preventing toxicity and promoting antioxidant and anti-inflammatory actions of bilirubin

Abstract

Bilirubin (BR) is the final product of haem catabolism. Disruptions along BR metabolic/transport pathways resulting from inherited disorders can increase plasma BR concentration (hyperbilirubinaemia). Unconjugated hyperbilirubinemia may induce BR accumulation in brain, potentially causing irreversible neurological damage, a condition known as BR encephalopathy or kernicterus, to which newborns are especially vulnerable. Numerous pharmaceutical strategies, mostly based on hemoperfusion, have been proposed over the last decades to identify new valid, low-risk alternatives for BR removal from plasma. On the other hand, accumulating evidence indicates that BR produces health benefits due to its potent antioxidant, anti-inflammatory and immunomodulatory action with a significant potential for the treatment of a multitude of diseases. The present manuscript reviews both such aspects of BR pharmacology, gathering literature data on applied pharmaceutical strategies adopted to: (i) reduce the plasma BR concentration for preventing neurotoxicity; (ii) produce a therapeutic effect based on BR efficacy in the treatment of many disorders.

Keywords: Bilirubin; antioxidant; hyperbilirubinaemia; jaundice.

Figure 1.

Bilirubin excretion pathway. MRP1, MRP3, MRP4, OATP1B1, and OATP1B3 are sinusoidal unconjugated and conjugated bilirubin transporters, whereas MRP2 and ABCG2 are implicated in its elimination in the biliary duct.

Figure 3.

Bilirubin biosynthetic pathway and antioxidant mechanism.

Figure 2.

Configurational photoisomerization of (4Z,15Z)-bilirubin (biosynthetic and water-insoluble form) to (4Z,15E)-, (4E,15Z)- and (4E,15E)- isomers. Structural photoisomerization of (4Z,15Z)-bilirubin to (Z)-lumirubin and configurational isomerisation of the latter to (E)-lumirubin are also shown. Black dashed lines represent intramolecular hydrogen bonds.

Figure 4.

A) X-ray solved structure of 4Z,15E-bilirubin-IX-α in complex with HSA (PDB 2VUE). B) Superposition of BR (cyan), naproxen (red, PDB 2VDB), indomethacin (green, PDB 2BXM), diclofenac (magenta, PDB 4Z69), ibuprofen (yellow, PDB 2BXG) and sulfasalazine (blue, PDB 6R7S) bound to HSA. H-bonds are depicted as black dashed lines. Amino acids are labelled with one letter symbols: F, Phe; I, Ile; K, Lys; L, Leu; P, Pro; R, Arg; V, Val; Y, Tyr.

Figure 5.

Production pathway for crosslinked chitosan spherical beads.

Figure 6.

Synthetic pathway for the production of CD-grafted polyethyleneimine as water-soluble adsorbent for BR removal.

Figure 7.

Synthetic approach adopted to attach PEG to BOX^,.

Figure 8.

Drugs administered per os to attain the reduction of BR serum concentration.

Figure 9.

Structure of bilirubin ditaurate (BRT).

Figure 10.

Synthesis of PEG-BR and formation of BRNPs upon self-assembly.

Figure 11.

Illustration of the preparation of ACUPA-SN38@BRNPs in aqueous solution upon self-assembly.

Figure 12.

Synthesis of ChiBil conjugate and ChiBil-losartan formation upon self-assembly.

Figure 13.

Illustration of PEGylated BR self-assembly to form d-SN38 and d-LND loaded nanoparticles, and their coadministration anti-PD-L1 and iRGD.

Figure 14.

Synthetic route for PLCDs and supramolecular inclusion of BR to yield PLCD-BR.