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Bilirubin: the Toxic Mechanisms of an Antioxidant Molecule

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Bilirubin: the Toxic Mechanisms of an Antioxidant Molecule Review Arch Argent Pediatr 2021;119(1):e18-e25 / e18 Bilirubin: The toxic mechanisms of an antioxidant molecule Constanza P. Soto Conti, M.D.a ABSTRACT GLOSSARY Hyperbilirubinemia is the most common reason BVR: biliverdin reductase. for consultation and hospitalization in the neonatal period. It requires a timely initiation of CNS: central nervous system. an effective treatment because newborn infants DB: direct (or conjugated) bilirubin. are especially vulnerable to damage caused by DNA: deoxyribonucleic acid. bilirubin in the central nervous system due to FIB: free indirect bilirubin (or the characteristics typical of this stage of life. High bilirubin levels result in neurotoxicity and bilirubin not bound to albumin). oxidative stress. However, molecular biology FR: free radical. studies have demonstrated that bilirubin itself HO: heme oxygenase. acts as a potent antioxidant. IB: indirect (or unconjugated) bilirubin. The objective of this update is to review the processes whereby bilirubin causes cell damage NBI: newborn infant. and determine its beneficial antioxidant effects. PNBI: preterm newborn infant. Knowing these mechanisms may facilitate a more RNA: ribonucleic acid. accurate indication of a customized, effective, TNF-α: tumor necrosis factor alpha. and timely phototherapy. Until new scientific advances are made, phototherapy should be TSB: total serum bilirubin. prescribed based on expert consensus. UGT1A1: uridine diphosphate Key words: bilirubin, neurotoxicity syndromes, glucuronosyltransferase 1A1. antioxidants, oxidative stress, newborn. http://dx.doi.org/10.5546/aap.2021.eng.e18 INTRODUCTION Hyperbilirubinemia is the most common reason for consultation To cite: Soto Conti CP. Bilirubin: The toxic mechanisms and hospitalization among newborn of an antioxidant molecule. Arch Argent Pediatr 2021; infants (NBIs), for whom it poses 119(1):e18-e25. potential neurological consequences, sometimes severe and irreversible, especially if they are preterm NBIs (PNBIs).1 The cellular and molecular mechanisms whereby bilirubin causes central nervous system (CNS) damage have been described over the years. However, many questions remain to a. Hospital Materno be answered.2-7 Infantil Ramón Bilirubin’s beneficial antioxidant Sardá. Autonomous effects have been described with City of Buenos Aires, Argentina. molecular biology techniques. In adults, an increase in total serum E-mail address: bilirubin (TSB) is a good prognosis Constanza P. Soto Conti, factor in some conditions; it has even M.D.: been speculated that it may be used in [email protected] future therapeutic options.8-11 Funding: It is worth noting that, in humans, None. bilirubin increases after birth, with the sudden changes in oxygen Conflict of interest: pressures and cellular oxidation.12 In None. turn, it is surprising that such potent Received: 5-29-2020 antioxidant sometimes behaves in a Accepted: 8-18-2020 toxic manner. Bilirubin: The toxic mechanisms of an antioxidant molecule / e19 NBIs should be closely monitored and receive monoxide molecule and a biliverdin molecule. a timely and effective treatment based on the best Such reaction releases iron and consumes oxygen. available resources: expert recommendations, at Then, the biliverdin reductase (BVR) enzyme least until unanswered questions are resolved.13 reduces biliverdin to bilirubin. Thus formed, An update on the damage-causing mechanisms bilirubin is known as unconjugated or indirect and potential benefits of bilirubin may be useful bilirubin (IB). This is a hydrophobic molecule, so for those who prescribe phototherapy on a daily it binds to albumin to be transported to the liver, basis to reflect about how bilirubin works in the where it is conjugated with glucuronic acid. The setting of each NBI’s characteristics. glucuronidation process turns it into conjugated or direct bilirubin (DB) and makes it water- Bilirubin metabolism soluble so it can be incorporated into bile, which Bilirubin originates from heme-containing carries it to the gut. molecules. Eighty percent of heme comes from The gut bacterial flora turns DB into hemoglobin released by senescent red blood cells stercobilinogen and urobilinogen, pigments and an ineffective erythropoiesis. The remaining excreted through feces and urine. In the gut, 20 % comes from non-erythroid enzymatic before excretion, there is a possibility that DB sources: cytochromes, catalases, peroxidase, and may turn again into IB, due to the action of tryptophan pyrrolase.14 an enzyme called beta-glucuronidase, and then In the cells of the reticuloendothelial system, re-enter circulation as IB. This constitutes the the heme oxygenase (HO) enzyme hydrolyzes enterohepatic circulation of bilirubin9,12 (Figure 1). the heme molecule and turns it into a carbon Bilirubin levels measured in blood account for FIGURE 1. Metabolism of bilirubin production and recovery Reticuloendothelial system Bone marrow Senescent red blood cells Enzymes Ineffective erythropoiesis Heme Heme oxygenase Redox cycle (ERS) Biliverdin Cytochrome P450 Biliverdin reductase: (mitochondria): Oxidation: Reduction of biliverdin from bilirubin to biliverdin to bilirubin Bilirubin Free bilirubin + Albumin Detoxifies excess oxidants Glucuronosyltransferase Conjugated bilirubin Enterohepatic circulation of bilirubin Beta-glucuronidase Stercobilinogen ERS: endoplasmic reticulum system. The upper right part of the figure shows the level where the process occurs reversely with bilirubin being turned into biliverdin and capturing oxygen free radicals, thus resulting in an antioxidant effect. (Developed by the author). e20 / Arch Argent Pediatr 2021;119(1):e18-e25 / Review TSB concentrations, which is the sum of IB and encephalopathy), central hearing loss, and even DB. TSB levels include two fractions of IB: free death. In PNBIs, these conditions may occur with indirect bilirubin (FIB), which accounts for 0.01 % low bilirubin levels, cause subtle neurological of IB,9 and albumin-bound bilirubin. In clinical disabilities, and lead to manifestations that vary practice, there is no easily accessible lab test to even among patients born at the same gestational measure FIB, so therapeutic decisions are based age.17,18 on TSB levels.15 Bilirubin is lipid-soluble, passes through Bilirubin binding to albumin the membranes, and is incorporated to cells Albumin is the most common serum protein. and organs. In the setting of intrauterine life, It accounts for 50-60 % of total plasma protein this characteristic allows bilirubin to cross the in human beings. It binds to a wide variety of placental barrier from the fetus to the mother, endogenous and exogenous ligands, which it who excretes it through the liver.14 carries.19 Albumin-bilirubin binding is the main protective factor of cells; it depends on their levels Vulnerability characteristics of newborn infants and on albumin affinity for bilirubin.19,20 The human species is the only one that Only FIB, which is not bound to albumin, experiences a physiological bilirubin increase crosses the blood-brain barrier, passes through in the neonatal period. This is for two reasons: the membranes, and enters cells.20 FIB increases one is the physiological hemolysis caused as IB reaches its total albumin binding capacity by oxidative stress due to the change from (1 g of human serum albumin binds to 8 mg of IB placental to pulmonary oxygenation. In addition in term NBIs, but this is lower in PNBIs). to this aspect, some individuals occasionally Binding is reversible. The binding-unbinding experience immune or hereditary hemolysis. balance is dynamic and varies depending on pH The other reason is of metabolic origin, due and temperature.19 Conditions like hypothermia, to an increase in IB. The uridine diphosphate hypoxia, acidosis, and asphyxia favor neurotoxicity glucuronosyltransferase 1A1 (UGT1A1) enzyme by breaking the binding and generating FIB.21,22 conjugates bilirubin in the liver. There is evidence Certain drugs like ceftriaxone and ibuprofen of the presence of this enzyme in the small compete with bilirubin for albumin binding.19 A intestine and of its role in the glucuronidation of lipid intake of more than 1.5 g/kg significantly bilirubin in the enterocyte. reduces the bilirubin-albumin binding capacity Fujiwara et al. found, in exclusively breast- and increases FIB levels in PNBIs born at less than fed NBIs, a suppression of UGT1A1 expression 28 weeks of gestational age.21 In these patients, the in the enterocyte, a lower glucuronidation, an bilirubin-albumin ratio would be a better predictor increased enterohepatic circulation, and a greater of bilirubin-induced neurotoxicity than TSB levels, IB availability. This mechanism, which has not although further studies are required.19,21 been observed in formula-fed NBIs, highlights the physiological and antioxidant role of bilirubin in Cell toxicity by bilirubin response to the oxidative stress caused by birth.14 Bilirubin-induced neurotoxicity involves In addition, some NBIs may have hematoma complex cascades of molecular and cellular resorption, a low albumin level or a reduced events. It alters the blood-brain barrier and affects bilirubin-albumin binding capacity and/or some CNS regions particularly. It has multiple trouble establishing breastfeeding; such events effects on neurons and glial cells, cellular and favor increased bilirubin levels.2 mitochondrial membranes, and the endoplasmic In addition to what has been described, NBIs reticulum. It causes a failure in mitochondrial have a vulnerable CNS. In neonates,
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