Invited critical review
Bilirubin toxicity to human erythrocytes: A review

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Abstract

Neonatal jaundice, a physiologic condition reflecting the interplay between developmentally modulated changes in bilirubin production and metabolism, affects virtually all newborn infants. Usually, it is an entirely benign process that is resolved at the end of the first week of life without treatment or sequelae. However, in a small percentage of neonates, unconjugated hyperbilirubinemia can pose a neurotoxic risk especially in the presence of aggravating conditions such as a diminished albumin binding capacity and/or affinity, acidosis, displacing drugs and prematurity. Although neuronal cells are considered the main target for unconjugated bilirubin (UCB) toxicity, circulating cells are also affected during neonatal hyperbilirubinemia. Moreover, the UCB ability to cause hemolysis shall further aggravate neonatal jaundice through a vicious circle. In this review, we summarize the most relevant data obtained by our group regarding UCB toxicity and the role of some risk factors for kernicterus. In order to improve the risk assessment of neurotoxicity it is essential to understand the underlying mechanisms of UCB pathophysiology.

Section snippets

Bilirubin and neonatal jaundice

Bilirubin is the principal degradation end product of heme moiety from hemoglobin and other hemoproteins in mammals. Due to its structure, unconjugated bilirubin (UCB) is poorly soluble in aqueous medium (< 70 nM). Therefore, over 99.9% UCB is transported in the blood tightly bound to albumin and biotransformation is required for excretion [1], [2], [3]. Due to the augmented hemolysis and to the immaturity of the mechanisms for bilirubin disposition in the neonatal period, virtually all newborn

Conclusions

In this review, we show that in vitro exposure of human RBC to UCB induces profound disturbances of cell integrity and morphology and that cellular uptake of UCB is enhanced by the presence of the bilirubin-displacing drug, sulfisoxazole. These perturbations increase with the UCB to albumin molar ratio and with acidosis, pointing to diacid UCB as the cytotoxic species and implicating the UCB precipitates in the irreversible mechanisms of cytotoxicity. This late finding was corroborated by the

Acknowledgements

The authors wish to express their appreciation to all the co-authors of the publications, in which findings are described in this review. Studies from the authors' research unit were funded by Fundação para a Ciência e a Tecnologia (Portugal).

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