Toxic effects of unconjugated bilirubin (BR) in neonatal hyperbilirubinemia have been related to redox and/or
coordinate interactions with Cu2+. However, the development and mechanisms of such interactions at physiological
pH have not been resolved. This study shows that BR reduces Cu2+ to Cu1+ in 1:1 stoichiometry.
Apparently, BR undergoes degradation, i.e. BR and Cu2+ do not form stable complexes. The binding of Cu2+ to
inorganic phosphates, liposomal phosphate groups, or to chelating drug penicillamine, impedes redox interactions
with BR. Cu1+ undergoes spontaneous oxidation by O2 resulting in hydrogen peroxide accumulation and
hydroxyl radical production. In relation to this, copper and BR induced synergistic oxidative/damaging effects
on erythrocytes membrane, which were alleviated by penicillamine. The production of reactive oxygen species
by BR and copper represents a plausible cause of BR toxic effects and cell damage in hyperbilirubinemia. Further
examination of therapeutic potentials of copper chelators in the treatment of severe neonatal hyperbilirubinemia
is needed
