Xylose, Glucose, and Glucuronic Acid Conjugation of Bilirubin in the Newborn Rat (original) (raw)
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Pediatrics, 2002
Objective. The objective of this study was to evaluate the roles of production and conjugation of bilirubin, individually and in combination, in the mechanism of neonatal jaundice. Methods. A cohort of healthy, term male newborns was sampled on the third day of life, coincident with routine metabolic screening, for blood carboxyhemoglobin determination, a reflection of heme catabolism, and for serum unconjugated and conjugated bilirubin fractions, reflecting bilirubin conjugation. The former was determined by gas chromatography, corrected for inspired CO (COHbc), and expressed as percentage of total hemoglobin. Serum bilirubin fractions were quantified by alkaline methanolysis and reverse phase high performance liquid chromatography. The sum of all bilirubin fractions comprised serum total bilirubin (STB). Total conjugated bilirubin (TCB) was comprised of the sum of the conjugated fractions and was expressed as percentage of STB (TCB[%]). A “bilirubin production/conjugation index” (...
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 Clinical Investigation, 1978
A B S T R A C T The microsomal enzyme uridine diphosphate (UDP) glucuronate glucuronyltransferase (E.C. 2.4.1.17) catalyzes formation of bilirubin monoglucuronide from bilirubin and UDPglucuronic acid. Bilirubin glucuronoside glucuronosyltransferase (E.C. 2.4.1.95), an enzyme concentrated in plasma membrane-enriched fractions of rat liver, converts bilirubin monoglucuronide to bilirubin diglucuronide. Bilirubin glucuronoside glucuronosyltransferase activity was studied in homogenates of liver biopsy specimens obtained from patients with the Crigler-Najjar syndrome (Type I) and in subcellular liver fractions of rats homozygous for UDPglucuronate glucuronyltransferase deficiency (Gunn strain). In patients with the Crigler-Najiar syndrome (Type I) and in Gunn rats, hepatic UDPglucuronate glucuronyltransferase activity was not measurable; however, bilirubin glucuronoside glucuronosyltransferase activity was similar to that in normal controls. The subcellular distribution of bilirubin glucuronoside glucuronosyltransferase activity in Gunn rat liver was similar to the distribution observed in normal Wistar rat liver.
Neonatal Jaundice: Bilirubin Physiology and Clinical Chemistry
NeoReviews, 2007
Objectives After completing this article, readers should be able to: 1. Identify the sources and chemical forms of bilirubin in the body. 2. Delineate the normal metabolic pathways for bilirubin production. 3. Describe how bilirubin is transported in the body. 4. Delineate the normal metabolic pathway for bilirubin excretion. 5. Differentiate and appreciate the limitations of the various methods used to measure bilirubin.
Archives of Disease in Childhood - Fetal and Neonatal Edition, 2005
To evaluate relations between production and conjugation of bilirubin in the pathophysiology of jaundice in glucose-6-phosophate dehydrogenase (G6PD) deficient neonates. Methods: Term and borderline premature (35-37 weeks gestational age), healthy, male, G6PD deficient neonates were studied close to the beginning of the 3rd day. Blood carboxyhaemogobin corrected for inspired CO (COHbc; an index of bilirubin production) and serum total conjugated bilirubin (TCB; a reflection of bilirubin conjugation) were measured in simultaneously drawn blood samples by gas chromatography and reverse phase high performance liquid chromatography respectively. A bilirubin production-conjugation index comprising COHbc/TCB was determined; a high index reflects imbalance between the bilirubin production and conjugation processes. COHbc and TCB individually and the production-conjugation index were studied in relation to serum total bilirubin (STB) concentration. Results: Fifty one G6PD deficient neonates were sampled at 51 (8) hours. COHbc values did not correlate with STB (r = 0.22, p = 0.15). TCB did correlate inversely with STB (r = 20.42, p = 0.004), and there was a positive correlation between the production-conjugation index and STB (r = 0.45, p = 0.002). The production-conjugation index (median (interquartile range)) was higher in the premature (n = 8) than term neonates (2.31 (2.12-3.08) v 1.05 (0.53-1.81), p = 0.003). This difference was the result of changes in TCB. Conclusions: The data show that jaundice in G6PD deficient neonates is the result of an imbalance between production and conjugation of bilirubin with a tendency for inefficient bilirubin conjugation over increased haemolysis in its pathogenesis. Borderline premature infants are at especial risk of bilirubin production-conjugation imbalance.
In Vitro Induction of Bilirubin Conjugation in Primary Rat Hepatocyte Culture
Biochemical and Biophysical Research Communications, 2002
UDP-glucuronosyltransferase (UGT1A1) is a critical enzyme in the elimination of bilirubin. The aim of our study was to investigate bilirubin conjugation in primary rat hepatocyte culture and the in vitro inducibility of this isoenzyme by inducing compounds of different classes: dexamethasone, clofibrate, rifampicin, and methylcholanthrene. Hepatocytes exhibited a marked decline in UGT1A1 activity in the first 4 h of culturing