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PubMed1989

Degradation of plasma bilirubin by a bilirubin oxidase derivative which has a relatively long half-life in the circulation.

To enhance degradation of unconjugated bilirubin in hyperbilirubinemic subjects, we synthesized a bilirubin oxidase (EC 1.3.3.5) (BO) derivative (PEGBO) by covalently linking (2,4-bis[O-methoxy(polyethyleneglycol)]-6-chloro-s-triazine) (PEG) to the enzyme. Intravenously injected BO in rats disappeared from the circulation with a half-life of 2.5 min; the half-life of PEGBO was 190 min. Intravenously injected BO minimally and transiently decreased plasma bilirubin levels in jaundiced Gunn rats and in bile-duct-ligated jaundiced rats. In contrast, PEGBO rapidly and substantially decreased plasma bilirubin levels and the effect persisted for longer than 3 h. Renal dysfunction often occurs in patients with liver diseases. To study the role of bilirubin toxicity for the kidney, functions of transtubular transport for organic anions was measured in bile-duct-ligated jaundiced animals before and after treatment with PEGBO. Bile duct ligation decreased urinary excretion of phenolsulfophthalein (PSP), an organic anion used for renal function test. Treatment of the jaundiced animals with PEGBO increased the rate of PSP disappearance from the circulation and normalized its urinary excretion. Thus, PEGBO might be useful for the study of bilirubin toxicity in jaundiced animals.

Animals↗
PubMed1980

Clinical relevance of the plasma reserve albumin binding capacity for bilirubin (RABC) and "free" bilirubin concentration.

An analysis of 55 plasma samples from 46 jaundiced newborn infants showed that endogenous "free" bilirubin levels bear no significant correlation to reserve albumin binding capacities for bilirubin as determined by both the Sephadex G-25 gel filtration and the enzymatic peroxidation technique (r = 0.14, p less than 0.05). This contrasts with the significant correlation between the "free" bilirubin concentrations and the bilirubin/albumin molar ratios in the same plasma samples (r = 0.75, p less than 0.001). The results of this study suggest that if "free" bilirubin is the "driving force" in the pathogenesis of bilirubin encephalopathy then the use of the reserve albumin binding capacity for bilirubin as the only guide in predicting the risk of kernicterus may not be adequate.

Bilirubin↗
PubMed1984

Radioassay of UDP-glucuronyltransferase-catalysed formation of bilirubin monoglucuronides and bilirubin diglucuronide in liver microsomes.

A radioassay for specific determination of the rates of UDP-glucuronic acid-dependent conversion of bilirubin into the two isomeric (C-8, C-12) bilirubin monoglucuronides and bilirubin diglucuronide is described and illustrated by its application to rat liver microsomes. The method is based on measurement of the relative amounts of radiolabel in unesterified bilirubin and its mono- and di-esterified reaction products after incubation with [14C]bilirubin as substrate. This analysis is performed by the alkaline-methanolysis procedure, combined with one of two t.l.c. systems developed in order to enhance the sensitivity, accuracy and precision of the radioassay. Results for rates of total bilirubin glucuronide formation obtained with the new assay and the standard enzyme assay based on the ethyl anthranilate diazo-method were identical. However, the sensitivity of the latter technique is approx. 10-fold lower than that of the radioassay.

Animals↗
PubMed1987

Non-enzymic hydrolysis of bilirubin mono- and diglucuronide to unconjugated bilirubin in model and native bile systems. Potential role in the formation of gallstones.

Pigment gallstones contain considerable amounts of unconjugated bilirubin (UCB) in the form of calcium bilirubinate and/or bilirubin polymers. Since more than 98% of bile pigments are excreted as conjugates of bilirubin, the source of this UCB needs to be identified. By using a rapid h.p.l.c. method, we compared the non-enzymic hydrolysis of bilirubin monoglucuronide (BMG) and bilirubin diglucuronide (BDG) to UCB in model bile and in native guinea-pig bile. Model biles containing 50 microM solutions of pure BMG and BDG were individually incubated in 25 mM-sodium taurocholate (NaTC) and 0.4 M-imidazole/5 mM-ascorbate buffer (TC-BUF) at 37 degrees C. Over an 8 h period, BMG hydrolysis produced 4-6 times more UCB than BDG hydrolysis. At pH 7.4, 25% of the BMG was converted into UCB, whereas only 4.5% of BDG was converted into UCB. Hydrolysis rates for both BMG and BDG followed the pH order 7.8 greater than 7.6 approximately equal to 7.4 greater than 7.1 Incubation with Ca2+ (6.2 mM) at pH 7.4 in TC-BUF resulted in precipitated bile pigment which, at 100 X magnification, appeared similar to precipitates seen in the bile of patients with pigment gallstones. At pH 7.4, lecithin (crude phosphatidylcholine) (4.2 mM) was a potent inhibitor of hydrolysis of BMG and BDG. The addition of a concentration of cholesterol equimolar with that of lecithin eliminated this inhibitory effect. Guinea-pig gallbladder bile incubated with glucaro-1,4-lactone (an inhibitor of beta-glucuronidase) underwent hydrolysis similar to the model bile systems. The non-enzymic hydrolysis of bile pigments, especially BMG, may be an important mechanism of bile-pigment precipitation and, ultimately, of gallstone formation.

Animals↗
PubMed2003

Administration of drugs known to inhibit P-glycoprotein increases brain bilirubin and alters the regional distribution of bilirubin in rat brain.

P-glycoprotein (P-gp) is an ATP-dependent integral plasma membrane efflux pump, expressed in abundance in brain capillary endothelial cells and astrocytes. P-gp contributes to the blood-brain barrier in limiting the influx and retention of a variety of lipophilic compounds, including unconjugated bilirubin. Several drugs block P-gp function and thereby enhance intracellular accumulation of P-gp substrates. In this study we proposed that pretreatment with drugs known to inhibit P-gp function in clinically relevant doses would alter the uptake of bilirubin in the brain of 32- to 36-d-old rats. In the first arm of the study, the animals received pretreatment with an i.v. infusion of either propanolol, erythromycin, verapamil, ceftriaxone, rifampin, or saline, 10 min before an i.v. bolus of 50 mg/kg bilirubin was given. Except for the erythromycin-treated rats, all treatment groups had significantly higher brain-to-serum bilirubin ratios than control animals (p < 0.05, Welch's t test). In the second arm of the study, treatment with either ceftriaxone or rifampin or saline i.v. preceded a 50 mg/kg i.v. bolus of radioactive bilirubin. Analysis of seven different brain regions by scintillation counting showed that the distribution patterns differed significantly between the study groups (p < 0.001, ANOVA), however, not in accordance with a kernicteric staining pattern. Because of limited knowledge of expression and function of P-gp and other membrane transport proteins in the newborn, the implications of this study remain to be seen. We speculate that drugs known to inhibit P-gp function may increase the risk of bilirubin encephalopathy in the hyperbilirubinemic infant.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Bilirubin dehydrogenase, an enzyme in Aspergillus ochraceus IB-3 useful for diagnostic measurement of bilirubin.

Bilirubin dehydrogenase, a membrane-bound enzyme that catalyzes the one-step oxidation of ditaurobilirubin and bilirubin to ditaurobiliverdin and biliverdin, respectively, in the presence of an electron acceptor, was found in Aspergillus ochraceus IB-3, and purified from the membrane fraction through solubilization by Triton X-100. Phenazine and quinone derivatives acted as electron acceptors. Accumulation of ditaurobiliverdin and biliverdin by enzyme catalysis increased the absorbance at 660 nm, which is far from the range of wavelengths affected by serum ingredients. The enzyme selectively oxidized ditaurobilirubin at low pH, so changes in the reaction pH enable the enzyme to discriminate between the bilirubin fractions ditaurobilirubin (an example of conjugated bilirubin) and bilirubin (an example of unconjugated bilirubin). Using the enzyme, 2 to 80 microM of ditaurobilirubin were measured accurately by monitoring the changes in absorbance at 660 nm.

Aspergillus ochraceus↗
PubMed1975

Bilirubin as a cholestatic agent. III. Prevention of bilirubin-related cholestasis by sulfobromophthalein.

The administration of sulfobromophthalein sodium (BSP) to manganese-loaded animals had been found to prevent effectively the cholestasis normally created by bilirubin infusion following manganese loading. Measurement of bilirubin levels in blood, liver, and bile in manganese-bilirubin animals with and without BSP fails to provide convincing evidence for a BSP-induced shift in site or magnitude of total bilirubin concentration as an explanation for this anticholestatic action of BSP. Nevertheless, increasing the dose of bilirubin partially reinstitutes the cholestasis. The results are important in that they demonstrate (1) that under certain circumstances intrahepatic cholestasis can be immediately and directly prevented by a pharmacologic agent (by a means not as yet defined) and (2) that the cholestatic activity of bilirubin is, to some extent or under some circumstances, separable from its concentration in blood, liver, and bile.

Animals↗
PubMed1989

[A colorimetric method for determination of delta-bilirubin in serum using bilirubin oxidase (Trachyderma tsunodae)].

We developed a colorimetric method to measure delta-Bilirubin in human serum using bilirubin oxidase from Trachyderma tsunodae and diazo reagent. In the first step, bilirubin fractions except for delta-Bilirubin, such as diconjugated, monoconjugated and unconjugated forms, are removed by enzymatic oxidation at pH 8.0 in the presence of sodium salicylate. In the second step, delta-Bilirubin remaining after enzymatic oxidation is determined by the conventional indirect diazo method. The results obtained by this method showed intra-day CV of 2.4%, satisfactory linearity and good correlation (r = 0.93, p less than 0.001) with those obtained by high performance liquid chromatography method. This simple and rapid method was clinical useful for determining the bilirubin fractions in sera of hepatic patients.

Basidiomycota↗
PubMed1987

Determination of conjugated and total bilirubin in serum of neonates, with use of bilirubin oxidase.

A new, simple, and rapid assay for conjugated bilirubin that does not require serum-matrix standards was developed by using the enzyme bilirubin oxidase (EC 1.3.3.5). This procedure can also be modified to measure total bilirubin. Measurements from these assays were compared with results obtained with the Sigma 605 (Jendrassik-Gróf method), Sigma 550/551 (Walters-Gerarde method), and Kodak Ektachem (BuBc) bilirubin assays. The one-year study involved serum specimens from 283 infants younger than 30 days. Linear-regression analysis of data for conjugated bilirubin collected by this assay and by the Kodak Ektachem assay yielded a slope of 0.975, an intercept of 0.088, an Syx of 1.47 mg/L, and a correlation coefficient of 0.94 for a total of 49 specimens. Correlation was also good (r = 0.95) between results for total bilirubin by this assay and both the Sigma 605 and the Kodak Ektachem methods.

Bilirubin↗
PubMed1999

Enzymatic assay for conjugated bilirubin (Bc) in serum using bilirubin oxidase (BOD).

We described an automated enzymatic assay for conjugated bilirubin (Bc) in serum using the Iatro D-Bil kit, with bilirubin oxidase (EC 1.3.3.5 BOD) from Myrothecium species. The specificity of the enzyme in the Iatro D-Bil kit was examined by analyzing unconjugated bilirubin (Bu), delta bilirubin (Bdelta), and Bc with high-performance liquid chromatography (HPLC), before and after the enzymatic reaction using BOD. The within-assay coefficients of variation (CV) of this method were 0.58 to 5.00% (n = 20) at 1.4 to 155.8 micromol/L. Day-to-day Cvs ranged from 1.61 to 7.14% at 1.2 to 182.1 micromol/L. The analytical recovery was 96 to 101%. The presence of ascorbic acid, reduced glutathione, L-cysteine, uric acid, urea, creatinine, glucose, lipemic material, anticoagulants, hemoglobin, or human serum albumin did not affect this assay system. The correlation coefficient between values obtained with the Iatro D-Bil kit (y) and HPLC method as reference for conjugated fractions (x) was; r = 0.983, y = 0.952x + 8.851 micromol/L, Sy/x = 11.97 (n = 56). We studied serum Bc levels, not including Bu and Bdelta, in patients with hepatic diseases or autoimmune hemolytic anemia. Levels of Bc obtained by the proposed method changed more rapidly than did those of direct bilirubin (D-Bil) obtained by diazo-dye method during the course of the diseases.

Anemia, Hemolytic↗
PubMed1986

Interaction of bilirubin with human lymphocytes and granulocytes--the effect on bilirubin metabolism.

An in vitro degradation of bilirubin by isolated human granulocytes and lymphocytes is described. Changes in the bilirubin concentration during interaction with these cells were determined spectrophotometrically. The dependence of the reaction velocity on the original bilirubin concentration followed an adsorption isotherm, typical of enzyme processes with a Km of 79 microM at a cell concentration of 500/microL. The primary event is the adsorption of bilirubin to the cell surface and, in addition, its detoxication. Cyanide and sonic treatment of cells inhibit the reaction, salicylic acid enhances the cell activity. The bilirubin-detoxicating effect is discussed with respect to the therapy of hyperbilirubinaemia in neonates.

Bilirubin↗
PubMed1988

Circular dichroism of bilirubin-amine association complexes: insights into bilirubin-albumin binding.

Bichromophoric (4Z, 15Z)-bilirubin-IX alpha, the yellow-orange cytotoxic pigment of jaundice, adopts either of two intramolecularly hydrogen-bonded enantiomeric conformations that are in dynamic equilibrium in solution. The addition of optically active amines induces the pigment solutions to exhibit intense bisignate circular dichroism in the region of the bilirubin long wavelength uv-visible absorption band. The most intense circular dichroism Cotton effects, (delta epsilon) approximately equal to 130, are induced by beta-arylamines and are comparable to those exhibited by bilirubin complexes with serum albumin and other proteins. Like serum albumin and other proteins, the optically active base acts as a chiral complexation agent to induce an asymmetric transformation of bilirubin, whose induced bisignate circular dichroism Cotton effect is characteristic of exciton splitting of the component pyrromethenone chromophores. The amines thus serve as chiral templates for molecular recognition, and the complementary action of the amine complexation sites provides insight into the binding forces important in protein-bilirubin heteroassociation.

Amines↗
PubMed1983

The binding of bilirubin to albumin. A study using spin-labelled bilirubin.

Binding between human serum albumin and a spin-labelled derivative of bilirubin was investigated by circular dichroism, fluorescence quenching, electron spin resonance and visible spectroscopy. The orders of magnitude of the binding constants obtained by flurorescence quenching and electron spin resonance spectroscopies were 10(7) and 10(3) 1 . mol-1, respectively. These data suggest that most spin-labelled bilirubin interacts with human serum albumin at the side not holding the spin-labelled side-arm. CD measurements showed the presence of at least two sites, associated with opposite Cotton effects. It is worthy of note that the Cotton sign of the first site is inverted with respect to the corresponding one of bilirubin. CD measurements on mixed systems (spin-labelled bilirubin/human serum albumin/bilirubin) were also performed. The decomposition of the ternary curves shows that the rotatory power of bilirubin bound to human serum albumin is higher in the ternary system than in the binary (bilirubin/human serum albumin). The corresponding CD measurements for the binding between spin-labelled bilirubin and bovine serum albumin are also reported and discussed.

Animals↗
PubMed1982

Risk of bilirubin acid precipitation in preterm infants with respiratory distress syndrome: considerations of blood/brain bilirubin transfer equilibrium.

Twenty-six preterm infants with respiratory distress syndrome (RDS), were examined daily during the first 6 days of life. Twenty-six equally preterm but clinically well infants served as controls. In the RDS infants, plasma albumin concentration was low, hyperbilirubinemia was prolonged, plasma pH was decreased during the first two days, and the concentration of reserve albumin for binding of monoacetyldiaminodiphenylsulfone (MADDS), a deputy ligand for bilirubin, was decreased on the second throughout the sixth day, when compared with the controls. These factors concur in increasing the likelihood of bilirubin acid precipitation in RDS above the increased risk present in preterm infants. The plasma of the preterm controls was supersaturated with respect to crystalline bilirubin acid by an average factor 5 (index of plasma bilirubin toxicity = 0.7) on the first day of life, peaking at a factor 10 (index 1.0) on the third and fourth days while these factors were 10 and 20 (index 1.0 and 1.3), respectively, in the RDS infants. Two of the latter surpassed a level of 60 times supersaturation (index 1.8) where acute precipitation of amorphous bilirubin acid becomes possible.

Bilirubin↗
PubMed1996

Cytotoxicity of bilirubin for human fibroblasts and rat astrocytes in culture. Effect of the ratio of bilirubin to serum albumin.

The sensitivity of rat brain astrocytes and human fibroblasts in culture to unconjugated bilirubin was investigated. Medium containing 6 mumol/1 bilirubin and increasing concentrations of human serum albumin giving ratios of 0.5-1.5 that resulted in an increase of the free bilirubin concentrations. The LDH activity in the culture medium was an index of cytolysis and the MTT assay was used as an index of mitochondrial impairment. The ratios producing half-maximum cell lysis after 24, 48, and 72 h, were 1.1, 0.9 and 0.85, for astrocytes, and 1.2, 0.75 and 0.75, for fibroblasts. Mitochondrial activity decreased after 24 h for ratio = 0.7 and partly recovered at 48 h. Mitochondrial activity was more impaired in fibroblasts than in astrocytes above ratio = 0.7. The cytotoxic effects were linked to the free bilirubin concentration. We conclude that astrocytes are less sensitive to bilirubin cytotoxic effects than are fibroblasts.

Animals↗
PubMed1983

Influence of free fatty acids and glucose infusion on serum bilirubin and bilirubin binding to albumin: clinical implications.

We studied the risk of a large group of jaundiced neonates for bilirubin encephalopathy by serial assessment of their reserve serum albumin binding capacity as measured by the saturation index test. In 1271 infants with serum bilirubin concentration greater than 10 mg/dl, 12% had a saturation index (SI) of 7% or greater and therefore were clinically at or near risk for bilirubin encephalopathy. Treatment with glucose infusion (1 gm/kg over one hour) was highly effective in lowering the SI (delta = -3.7%. P less than 0.001). In none of the infants did SI rebound to 7% or greater within 24 hours after the infusion. In a detailed study of 19 infants who received glucose, the highly significant (P less than 0.001) fall in SI (delta = -3.7%) was accompanied by an equally significant rise in serum values for insulin (delta = +21.6 mcu/ml) and fall in serum free fatty acids (delta = -0.51 mEq/L). Many factors in the study, such as prematurity, hemolysis, acidosis, and hypoxemia, could have predisposed the infants to the risk of bilirubin encephalopathy. However, the facility by which most (93%) of the infants with high SI, including those who were premature or had evidence of hemolysis or respiratory insufficiency, responded to infusion of glucose indicates that serum free fatty acids may be the principal factor contributing to the high saturation index and therefore an underestimated factor in bilirubin binding to albumin.

Bilirubin↗
PubMed1984

Quantitation of bilirubin conjugates with high-performance liquid chromatography in patients with low total serum bilirubin levels.

Bilirubin mono- and diconjugates were determined by alkaline methanolysis and high-performance liquid chromatography (HPLC) in serum from patients with metastatic liver disease and liver cirrhosis. Conjugates could be detected and quantitated at normal or low total bilirubin levels. Comparison with serum alkaline phosphatase activity revealed that in cirrhosis bilirubin conjugates were sometimes detectable at normal or slightly elevated alkaline phosphatase activities. In patients with metastatic liver disease alkaline phosphatase activity was a more sensitive indicator. In normal controls and in patients with Gilbert's syndrome no bilirubin conjugates were detected whereas serum of patients with haemolysis contained conjugated bilirubin. Therefore HPLC appears to be an excellent method to diagnose Gilbert's syndrome. In liver cirrhosis HPLC is a useful liver function test.

Bilirubin↗
PubMed1989

Kinetics of bilirubin oxidation catalysed by bilirubin oxidase in a water-in-oil microemulsion system.

1. Bilirubin oxidase can catalyse the oxidation of its primary substrate, bilirubin, in a water-in-oil microemulsion, which consists of discrete nanometer-diameter water droplets dispersed in a continuous water-immiscible oil medium. The droplets are stabilized by a monolayer of the surfactant, cetyltrimethylammonium bromide present at the oil/water interface. 2. Spectroscopic evidence is presented to show that bilirubin solubilized in this system is located mainly in the surfactant layer, in a form accessible to the enzyme molecule. 3. Studies are presented on the enzyme-catalysed rate of bilirubin oxidation in this system, as a function of temperature, pH, water content, and substrate and enzyme concentrations. 4. The main conclusions are that the enzyme can efficiently oxidise bilirubin in microemulsions of low water content. The reaction obeys Michaelis-Menten kinetics. The optimal pH for the catalysis is 8.0. The efficiency of catalysis decreases sharply as the water content increases.

Bilirubin↗