Disorders of Bilirubin Metabolism (original) (raw)
Related papers
Bilirubin metabolism: Applied physiology
Current Paediatrics, 2006
Bilirubin is the breakdown product of the haem moiety of haemoglobin and other haemoproteins. Because of internal hydrogen bonding, bilirubin is water-insoluble and requires enzyme-mediated glucuronidation in the liver for biliary excretion. In normal circumstances, plasma bilirubin is mostly unconjugated and is tightly bound to circulating albumin. It is taken up by hepatocytes by facilitated diffusion, stored in hepatocytes bound to glutathione-S-transferases and conjugated to glucuronides by microsomal UGT1A1. Bilirubin glucuronides are actively transported into the bile canaliculi by the ATP-utilizing pump MRP2. Bilirubin is degraded in the intestine by bacteria into urobilinogens, which are partly excreted in the urine. Increased production, reduced uptake and low glucuronidation capacity can increase plasma unconjugated bilirubin levels. In cases of inherited or acquired deficiencies of bilirubin storage or excretion, both conjugated and unconjugated bilirubin accumulate in the plasma. Conjugated bilirubin is less tightly bound to albumin and is excreted in the urine. The capacities of the various steps of bilirubin throughput are finely balanced, and the expression of the gene products mediating these steps is coordinated by nuclear receptors.
The biology of bilirubin production: detection and inhibition
Pediatric Medicine, 2021
Newborn jaundice is a benign condition commonly seen in the first postnatal week of life (or the transitional period). It is primarily due to an imbalance between the rate of production of the yellow-orange pigment bilirubin and its elimination by the liver. Infants with high bilirubin production rates (such as those who are undergoing hemolysis) or with insufficient hepatic bilirubin conjugating ability [such as those with uridine 5'-diphosho-glucuronosyltransferase (UGT1A1) deficiencies] can subsequently develop excessive circulating total serum/plasma bilirubin (TB) levels or hyperbilirubinemia. Bilirubin is formed during the degradation of heme, derived from the turnover of red blood cells (RBCs). In this reaction, which is catalyzed by the rate-limiting enzyme heme oxygenase (HO), carbon monoxide (CO), iron (Fe 2+), and bilirubin are produced in equimolar quantities. As a result, measurements of total body CO production rates can be used as indices of bilirubin production. Standard treatment strategies for hyperbilirubinemia involves the use of phototherapy (specifically narrow-band blue wavelength light) and/or exchange transfusion. However, if infants with excessive hyperbilirubinemia are not identified or treated in a timely manner, they are at risk for developing bilirubin neurotoxicity, which can manifest as bilirubin-induced neurologic dysfunction (BIND) and result in neurologic sequelae (such as acute or chronic bilirubin encephalopathy. Here, we review the biology of bilirubin production and current technologies and approaches to identify and treat these high-risk infants.
The pharmacological features of bilirubin: the question of the century
Cellular and Molecular Biology Letters, 2015
This review looks at the toxicity and metabolism of bilirubin in terms of its pharmacological potential. Its role has gained importance as more research has revealed the functional significance and interrelationship between the gasotransmitters nitric oxide and carbon monoxide. The biological actions of bilirubin have mostly been characterized in the high micromolar range where toxic effects occur. However, it could also prove to be an important cytoprotector for brain tissue, which is inherently less equipped for antioxidant defense. Plasma bilirubin levels negatively correlate to a number of disease states. Higher levels of bilirubin that are still within the normal range provide a protective effect to the body. The effects on various disorders could be tested using controlled pharmacological upregulation of the molecule with animal models. At nanomolar concentrations, considerable benefits have been obtained when the molecule was delivered pharmacologically under in vitro or in v...
Hepatology, 1996
three strains of mutant rats with congenital conjugated The workshop covered three major areas: Unconjuhyperbilirubinemia. (2) The roles of the classical and gated bilirubin (UCB) chemistry and physical chemistry; newer molecular biological approaches to identification UCB transport and intracellular trafficking; and evaluaof these transporters were contrasted, and their limitation and therapy of neonatal and congenital hyperbilitions were discussed. (3) The relative roles of the multirubinemias. Findings of studies in the chemistry and ple carriers in UCB transport under different conditions physical chemistry area were as follows. (1) Nuclear and substrate concentrations were discussed. (4) Cytomagnetic resonance (NMR) studies of highly enriched solic UCB-binding proteins (e.g., ligandin) were shown 13 COOH mesobilirubin in water-dimethyl sulfoxide systo promote transcellular movement of UCB by solubiliztems indicated that the pK a values of the carboxyl ing and transporting the pigment in the aqueous phase groups are 4.2 and 4.9, respectively. This finding differs while limiting binding of UCB to the relatively immobile from some reports that suggest that the two pK a values membranes of cell organelles. (5) Mechanisms were prein aqueous systems are near or above pH 7.0. (2) Consented for translocation of UDP-glucuronic acid (UDtrasting views of the hydrophobic interactions of UCB PGA) into the lumenal location of UDPGA transferase with bile salts were presented: one suggested that multiin the endoplasmic reticulum, as well as the enhanceple bile salt monomers bind to one UCB molecule; the ment of this process by N-acetyl-glucosamine. Studies other suggested that UCB binds to the nonpolar surface in the neonatal and congenital jaundice area were as of helical bile salt micelles. (3) Structures were proposed follows. (1) Criteria were reviewed for initiating treatfor the varied calcium and copper bilirubinate salts ment of neonatal jaundice, emphasizing the primacy of formed at various pH values and cation/UCB ratios. (4) serum bilirubin levels, gestational age, and hemolysis Studies of binding of UCB to human serum albumin as risk factors for kernicterus. (2) New methods were (HSA) showed marked diminution of UCB-binding affinpresented for frequent, automated monitoring of serum ity as albumin and chloride concentrations increased. bilirubin levels and breath CO levels as an index of rates (5) A unique UCB derivative, bilirubin-C10-sulfonic acid, of formation of UCB from heme. (3) The current status was identified as the major bile pigment in bullfrog bile. and limitations of new approaches to treatment of se-(6) New methods were presented for removal of impurivere unconjugated hyperbilirubinemia were discussed: ties from preparations of bile salts and UCB. Findings hepatocyte transplantation and gene therapy, still in the of studies in the transport area were as follows. (1) Four stage of development in animal models, have provided putative basolateral and two putative canalicular hepaonly partial and temporary relief of hyperbilirubinemia; tocytic transporters of UCB and related organic anions extracorporeal liver assist devices have had some sucwere described. Special emphasis was given to the adencess in initial human studies; and inhibition of heme osine triphosphate (ATP)-dependent canalicular multioxygenase (HO) with metalloporphyrins, especially tin specific organic anion transporter that is defective in mesoporphyrin, which markedly decreases bilirubin production for prolonged periods, is a new alternative Abbreviations: UCB, unconjugated bilirubin; NMR, nuclear magnetic resonance; NOE, to phototherapy. (4) The ontogeny of the two HO isonuclear Overhauser enhancement; DMSO, dimethyl sulfoxide; TC, taurocholate; CMC, criti-zymes was contrasted in the liver, spleen, kidney, and cal micellar concentration; CD, circular dichroism; Bf, concentration of unbound UCB; Kf,
Journal of Biological Chemistry, 2001
Biliverdin reductase (BVR) reduces heme oxygenase (HO) activity product, biliverdin, to bilirubin. BVR is unique in having dual pH/dual cofactor requirements. Using Escherichia coli-expressed human BVR and COS cells, we show that BVR is autophosphorylated and that phosphorylation is required for its activity. An "in blot" autophosphorylation assay showed that BVR is a renaturable phosphoprotein. Controls for the experiments were HO-1 and HO-2; both are phosphoproteins but are not autophosphorylated. Autophosphorylation was pH-dependent, with activity at pH 8.7 being most prominent. In addition, 2(3)-O-(2,4,6-trinitrophenyl)adenosine 5-triphosphate fluorescence titration of BVR gave a lower K d at pH 8.7 than at pH 7.4 (15.5 versus 28.0 M). Mn 2؉ was required for binding of the ATP analogue and for autophosphorylation; the autokinase activity was lost when treated at 60°C for 10 min. The loss of transferred phosphates by alkaline treatment suggested that BVR is a serine/threonine kinase. Potato acid phosphatase treatment reversibly inactivated the enzyme.
Circulation, 2005
Background— Bilirubin, a natural product of heme catabolism by heme oxygenases, was considered a toxic waste product until 1987, when its antioxidant potential was recognized. On the basis of observations that oxidative stress is a potent trigger in vascular proliferative responses, that heme oxygenase-1 is antiatherogenic, and that several studies now show that individuals with high-normal or supranormal levels of plasma bilirubin have a lesser incidence of atherosclerosis-related diseases, we hypothesized that bilirubin would have salutary effects on preventing intimal hyperplasia after balloon injury. Methods and Results— We found less balloon injury–induced neointima formation in hyperbilirubinemic Gunn rats and in wild-type rats treated with biliverdin, the precursor of bilirubin, than in controls. In vitro, bilirubin and biliverdin inhibited serum-driven smooth muscle cell cycle progression at the G 1 phase via inhibition of the mitogen-activated protein kinase signal transduc...