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PubMed1999

Exploring the conformation of bilirubins with natural and unnatural analogues: use of positional and bridged isomers of bilirubin IXalpha.

Unlike bilirubin IXalpha (1), the isomers bilirubin IXdelta (2) and neobilirubin IXbeta (3) do not require conjugation with glucuronic acid in order to be excreted. A conformational analysis employing an optimized Monte Carlo method and a mixed Monte Carlo stochastic dynamics reveals that isomer 2 exhibits a structure more closed than the well known 'ridge-tile' conformation of 1. The change in the position of both propionic acid chains causes the loss of at least four hydrogen bonds. On the other hand, the change in the configuration of the distal dipyrrinone and the blockage of the lactamic nitrogen by the presence of a bridge in isomer 3 results in an open and more elongated structure, where the chance of hydrogen bond formation in this region is obliterated. The resulting molecular models for these compounds are consistent with 1H NM R, UV-vis, and TLC data.

Animals↗
PubMed2003

Orlistat treatment increases fecal bilirubin excretion and decreases plasma bilirubin concentrations in hyperbilirubinemic Gunn rats.

OBJECTIVE: To determine whether serum levels of unconjugated bilirubin (UCB) can be decreased by enhancing fecal fat excretion. STUDY DESIGN: Gunn rats were fed a high-fat diet (control) or the same diet mixed with the lipase inhibitor orlistat. At regular intervals, plasma UCB concentrations were determined and 72-hour fat balances were performed. RESULTS: Orlistat treatment decreased plasma UCB concentrations (at 3 weeks; 100 mg/kg, -33%+/-8%, P<.05; 200 mg/kg, -46%+/-10%, P<.01). Within days of treatment, orlistat treatment increased fecal excretion of UCB (at day 3; +220%, P<.05). During 24 weeks of orlistat treatment (200 mg/kg diet), the plasma bilirubin concentrations were continuously approximately 35% lower than in control rats. Plasma UCB concentrations were inversely correlated with the amount of fecal fat excretion (n=12, r=-0.87, P<.001). CONCLUSIONS: In Gunn rats, orlistat treatment increases the fecal excretion of fat and enhances the disposal of UCB. This approach could lead to novel strategies for prevention and treatment of unconjugated hyperbilirubinemia in patients.

Animals↗
PubMed1979

Studies of human liver bilirubin-glycosyl transferase. Bilirubin UDP-xylosyl and UDP-glucuronyl transferase activities in diseased human livers.

The activity of bilirubin UDP-xylosyl transferase as well as UDP-glucuronyl transferase in liver biopsy specimens of 3 control subjects, 42 cases with liver disease and 5 cases with Gilbert's syndrome was measured. Normal values of these enzyme levels were determined to be 142--302 U/kg protein for the former and 260--400 U/kg protein for the latter. Both enzyme levels in acute hepatitis in convalescence and chronic hepatitis were nearly in the normal range. In the cirrhotic liver they tended to a small decrease and patients with Gilbert's syndrome demonstrated significantly decreased enzyme levels. These enzyme levels were only correlated with serum unconjugated bilirubin concentration, but not with the other liver function tests. Finally, both enzyme activities were exactly correlated with each other.

Bilirubin↗
PubMed1992

Ionization and self-association of unconjugated bilirubin, determined by rapid solvent partition from chloroform, with further studies of bilirubin solubility.

Our studies of equilibrium solubilization of crystals of unconjugated bilirubin (UCB) in buffered aqueous NaCl (1988. J. Lipid Res. 29: 335-348) suggested that the two carboxylic pKa values were 6.8 and 9.3 and the solubility of UCB diacid was 0.1 microM. These data, however, were not ideal, due to possible effects of crystal size, metastability, 96-h incubation times with formation of polar derivatives, impurities in the bilirubin, and imprecision of analyses at low concentrations of UCB ([UCB]). In the present study, designed to determine the pKa values and self-association of UCB, these problems were minimized by solvent partition of UCB from solution in CHCl3 into buffered aqueous NaCl. There was no crystal phase. Equilibrium was attained rapidly (10 min); UCB and CHCl3 were highly purified; and accurate diazo assay of low [UCB] in the aqueous phase, [Bw], was achieved by concentrating the UCB through back-extraction into a small volume of CHCl3. By determining effects on partition rations of varying the [UCB] in the CHCl3 phase, [Bc], we could assess also the self-association of UCB species in the aqueous phase. Partition ratios (P = Bw/Bc) did not differ between initial and repeat extractions, indicating insignificant concentrations of polar UCB derivatives. Similar P ratios were obtained when equilibrium was approached from a supersaturated aqueous phase. At 21-25 degrees C, mu = 0.15, the data (n = 76) fit the equation: log P = log Po + log[1 + 10(pH-A) + 10(2pH-B) + Bc.10(4pH-D)]; the bracketed terms reflect P for H2Bo (diacid), HB- (monoanion), B= (dianion), and (B=)2 dimer, respectively. Computer-fitted values for constants (+/- SD) were: Po = P for H2Bo = 5.79 x 10(-5); A = pK1 = 8.12 +/- 0.23; B = pK1 + pK2 = 16.56 +/- 0.10; pK2 = 8.44 +/- 0.33; D = pk22 + 2(pK1 + pK2) -log(2Po) = 37.64 +/- 0.07, and k22 = 0.26 microM-1 [formation constant of (B=)2 dimer]. In ancillary studies, multiple cycles of direct dissolution of UCB crystals revealed a progressive decrease in aqueous solubility of UCB as fine crystals were removed; this effect was minimal in CHCl3. Unlike in water, moreover, varied UCB crystal forms had similar solubilities in CHCl3, with [Bc] = 1.14 mM at saturation. As determined from [Bc]sat.Po, the aqueous solubility of H2Bo was 66 nM.(ABSTRACT TRUNCATED AT 400 WORDS)

Bilirubin↗
PubMed1984

Bilirubin interference in a peroxidase-coupled procedure for creatinine eliminated by bilirubin oxidase.

A colorimetric peroxidase-coupled procedure for determination of creatinine in human serum and urine is described. A 30-s sample pre-treatment with bilirubin oxidase eliminates interference from endogenous bilirubin. The 4-aminoantipyrine-2-hydroxy-3,5-dichlorobenzenesulfonate chromogen system of this method is about fourfold more sensitive than current procedures that involve monitoring NAD(P)H and nearly fivefold more sensitive than the traditional picrate procedures. Incorporation of a sample blank eliminates positive interference from endogenous creatine. Results of the proposed procedure are somewhat lower than those of the common kinetic or equilibrium picrate techniques, as would be expected because of the effects of the well-known interferences in the latter methods.

Autoanalysis↗
PubMed2003

Transient elevation of serum bilirubin (a heme oxygenase-1 metabolite) level in hemorrhagic stroke: bilirubin is a marker of oxidant stress.

Bilirubin (Bil) is the end product of heme catabolism. The production of Bil reflects heme oxygenase-1 expression in response to oxidative stress in various diseases. To assess the role of Bil as a marker of oxidative stress in cases of brain damage, we measured serum Bil concentrations in patients with hemorrhagic stroke. Serum levels of total Bil were measured in 20 subarachnoid hemorrhage patients with symptomatic vasospasms and in 23 patients with intracerebral hemorrhage; concentrations were measured every day for 14 consecutive days. Serum Bil levels were significantly elevated in the early phases in both groups. Moreover, transient elevation was observed on the day prior to the observation of clinical manifestations of symptomatic vasospasm after SAH. Bil, known to be a powerful antioxidant, was induced after hemorrhagic stroke, reflecting the intensity of oxidative stress. Plasma Bil concentrations might serve as a useful marker of oxidative stress in hemorrhagic stroke patients.

Bilirubin↗
PubMed1985

Study of bilirubin metabolism by high-performance liquid chromatography: stability of bilirubin glucuronides.

The stabilities of bilirubin (BR) glucuronide, monoglucuronide (BMG), and diglucuronide (BDG) were studied under various conditions by HPLC. In aqueous media, BMG showed a pronounced lability and was easily transformed into equimolar BDG and BR. It was proved by direct analysis of tetrapyrrole isomers that BDG and BR were formed from dipyrrole exchange of BMG molecules. All reducing agents examined (sodium ascorbate, cysteine, GSH, dithiothreitol, NADH, and NADPH) suppressed the transformation of BMG into BDG and BR. Bovine serum albumin and rat liver cytosol fractions also stabilized BMG strongly. BDG was fairly stable in aqueous media as compared with BMG. When BMG was incubated both with and without liver plasma membranes (N2 fraction) from Wistar rats, the formation rates of BDG and BR in both incubation mixtures were exactly the same. The composition of BDG and BR isomers was the same in both mixtures. Also, heat denaturation of the plasma membranes did not affect formation rates. Moreover, the reaction was completely inhibited by sodium ascorbate. These findings indicate that rat liver plasma membranes have no enzyme activity for BDG formation from BMG.

Animals↗
PubMed1983

Effect of bilirubin infusion on excretion of bilirubin and biliverdin in rabbits.

Intravenous infusion of bilirubin (BR) at 171 micrograms/min/kg into rabbits resulted in biliary concentration of BR increasing from 3.8 (control) to 243 mg/dl and BR excretion increasing from 1.7 to 66 micrograms/min/kg. BR infusion resulted in biliary concentrations of biliverdin (BV) increasing from 9.1 to 30 g/dl and BV excretion increasing from 4.2 to 8.2 micrograms/min/kg. BR infusion produced a progressive decline in bile flow. BV was the predominant bile pigment in control rabbits fed either an alfalfa-based or chlorophyll-free diet. These results imply that rabbits can oxidize BR to BV.

Animals↗
PubMed2003

Bilirubin and S-nitrosothiols interaction: evidence for a possible role of bilirubin as a scavenger of nitric oxide.

Bilirubin (BR), the final product of heme catabolism, plays a crucial role in the defense against reactive oxygen species in various cell types. In this study, we addressed the hypothesis that BR can act as a physiological scavenger of nitric oxide (NO), a gaseous mediator involved in many cellular functions and able to trigger the formation of reactive nitrogen species with pro-oxidant activity. We found that S-nitrosocysteine (SNOC) and S-nitrosoglutathione (GSNO), which have a half-life of 0.52+/-0.07 hr and 38+/-5 hr and release NO at a constant rate of 1.42+/-0.2 hr(-1) and 0.018+/-0.002 hr(-1), respectively, were able to decrease BR half-life in a concentration-dependent manner under physiological conditions. This effect appears to be dependent on NO formation as L-cysteine and GSH did not affect BR consumption and nitrite was four to five times less efficient than SNOC in reducing BR half-life. Oxyhemoglobin, a well-known scavenger of NO, protected BR from SNOC-mediated degradation. In addition, the reaction between SNOC/GSNO and BR modified the absorption spectrum of the bile pigment showing a gradual increase in the absorbance at 316 nm. This change in the BR spectrum indicates that the bile pigment could be a target for N-nitrosation reactions, since it resembles the modifications occurred when other molecules such as di-peptides and uric acid are nitrosated. Taken together, these data suggest that BR should not be considered only as an endogenous antioxidant but also as a molecule with the potential ability to counteract intracellular nitrosative stress reactions.

Analysis of Variance↗
PubMed1999

Uptake of [(3)H]bilirubin in freshly isolated rat hepatocytes: role of free bilirubin concentration.

Hepatocytic transport of physiological concentrations of unconjugated bilirubin (UCB) has not been determined in isolated liver cells. Initial uptake of highly purified [(3)H]UCB was measured in rat hepatocytes in the presence of human serum albumin at various free, unbound UCB concentrations, [UCB]. At [UCB]=42 nM (below aqueous solubility of 70 nM), uptake was strictly temperature dependent; this was much less evident at [UCB]=166 nM (supersaturated). At low, physiological UCB concentrations, specific UCB uptake showed saturative kinetics with an apparent K(m) of 41 nM, indicating carrier-mediated transport. With aqueous supersaturation, UCB entered hepatocytes mainly by passive diffusion.

Animals↗
PubMed2003

Behavior of various mammalian albumins towards bilirubin binding and photochemical properties of different bilirubin-albumin complexes.

Bilirubin (BR) binding properties of serum albumins from different mammalian species viz. human (HSA), equine (ESA), dog (DSA) and guinea pig (GPSA) were studied by absorption, fluorescence and CD spectroscopy. Whereas, a complex of BR with ESA produced maximum change, GPSA-BR complex showed weaker interaction as reflected from absorption and fluorescence spectroscopic data. Conformational analysis of these albumins by near- and far-UV CD spectra suggested similar structural characteristics (both secondary and tertiary structures) for ESA and HSA, whereas, DSA and GPSA had lower amounts of secondary and tertiary structures being minimum for GPSA. Photoirradiation results of BR-albumin complexes showed GPSA-bound BR more labile compared with other complexes, whereas, BR-ESA complex was found to be more stable against photoinduced chemical changes. Taken together, all these results suggest that chiroptical properties/stability of albumin bound BR varies with albumin species.

Albumins↗
PubMed2004

Bilirubin as an antioxidant: kinetic studies of the reaction of bilirubin with peroxyl radicals in solution, micelles, and lipid bilayers.

Bilirubin (BR) showed very weak antioxidant activity in a nonpolar medium of styrene or cumene in chlorobenzene. In contrast, BR exhibited strong antioxidant activity in polar media such as aqueous lipid bilayers or SDS micelles/methyl linoleate (pH 7.4), where the rate with peroxyl radicals, k(inh) = 5.0 x 10(4) M(-)(1) s(-)(1), was comparable to that with vitamin E analogues, Trolox, or PMHC. An electron-transfer mechanism accounts for the effect of the medium on the antioxidant properties of BR.

Antioxidants↗
PubMed2004

Auditory brainstem response detects early bilirubin neurotoxicity at low indirect bilirubin values.

When sedation, prematurity or other disease processes mask symptoms in the clinically ill newborn, serum bilirubin concentration is monitored as the sole indicator of kernicterus risk. This case emphasizes the value of auditory brainstem responses for the management of indirect hyperbilirubinemia complicated by prematurity, hemolytic anemia, asphyxia, and direct hyperbilirubinemia.

Bilirubin↗
PubMed1979

Kinetics of bilirubin oxidation with peroxidase, as applied to studies of bilirubin-albumin binding.

In the determination of unbound bilirubin by rate of oxidation with peroxidase, errors may be caused by (1) phenol, propylparaben, and phenothiazines (free radical acceleration), (2) haemoglobin (peroxidase effect), and (3) ascorbate (inhibition). Such errors may be diminished by dilution 1:40, or with an anti-oxidant, tert-butyl-p-hydroxyanisole, and ascorbate oxidase.

Ascorbate Oxidase↗
PubMed1997

Early changes in cutaneous bilirubin and serum bilirubin isomers during intensive phototherapy of jaundiced neonates with blue and green light.

We measured the changes in cutaneous bilirubin (Br) and serum Br photoisomers in two groups of 5 jaundiced newborn infants treated by intensive phototherapy (IP), one with blue light and the other with green light. Cutaneous Br was measured with a transcutaneous jaundice meter and photoisomers were measured by HPLC. Cutaneous Br decreased in the two groups as soon as IP began, and the skin was completely bleached within 3 h with blue light only. Rebound occurred which was more marked after blue light IP. The main serum photoproduct was the 4Z-15E isomer, which reached a steady-state level within 1 h in both groups, whereas the lumirubin and 4E-15Z Br concentrations were slightly higher after green light IP. These data indicate that blue light is more suitable for IP, although this is not clearly explained by the production of more lumirubin.

Bilirubin↗
PubMed1978

Studies on human liver bilirubin-UDP-glycosyl transferase. I. Assay methods for bilirubin-UDP-glucuronyl and -xylosyl transferases of human liver specimen.

Micromethods for estimation of bilirubin uridine diphosphate-glucuronyl and -xylosyl transferases in liver are described. With these methods, a liver specimen as small as 10 mg is sufficient for assay of either enzyme activity and 15 mg is sufficient for assay of both enzymes. Normal values for livers with minimal elevation of SGOT and minimal histological change were 0.260-0.400 U/g protein for glucuronyl transferase and 0.142-0.302 U/g protein for xylosyl transferase.

Bilirubin↗
PubMed1987

Endogenous esterification of bilirubin by liver microsomes. Evidence for an intramicrosomal pool of UDP-glucose and lumenal orientation of bilirubin UDP-glycosyltransferase.

Conjugation of natural bilirubin (BR) depends on a hepatic microsomal UDP-glycosyltransferase using UDP-Glc, UDP-xylose, and predominantly UDP-GlcA. We found that esterification of BR occurred when washed intact microsomes derived from rat or guinea pig liver were incubated with BR in the absence of added UDP-sugar. This endogenous esterification was shown to lead predominantly to formation of the two positional isomers of BR monoglucoside and displayed the same regioselectivity as found for the BR monoglucosides formed by microsomes incubated with a saturating concentration of added UDP-Glc. This finding and absence of endogenous esterification in liver microsomes from mutant rats lacking BR UDP-glycosyltransferase activities demonstrated that endogenous esterification depended on UDP-glycosyltransferase and indicated, therefore, that UDP-Glc was present in the intact microsomal vesicles. With UDP-Glc added to the extramicrosomal incubation medium, BR glucosidation was markedly enhanced when the membrane permeability barrier was disrupted by pretreatment of the microsomes with detergent, sonication, or Staphylococcus aureus alpha-toxin. In contrast, such membrane disruption resulted in abolishment of endogenous esterification of BR, and a direct relationship was found between impairment of endogenous esterification and degree of vesicle disruption, suggesting that the UDP-Glc on which endogenous esterification depended was present in the lumenal space of the microsomes. Kinetic evidence and absence of an effect of increasing the microsomal concentration of dolichol-P-Glc (Dol-P-Glc) on endogenous esterification excluded direct or indirect involvement of Dol-P-Glc in the endogenous esterification reaction. Preincubation of intact microsomes with UDP-Glc or UDP-xylose at 37 degrees C, but not at 0 degrees C, led to expansion of the microsomal UDP-sugar pool on which endogenous esterification depended, suggesting that both UDP-sugars can enter the microsomal vesicles by a temperature-dependent mechanism. In contrast to these findings, no increase of BR esterification was detected when the microsomes had been preincubated at 37 degrees C with UDP-GlcA. We conclude that native, intact microsomes contain a lumenal pool of endogenous UDP-Glc and that BR UDP-glucosyltransferase and UDP-xylosyltransferase, by virtue of a lumenal orientation, have direct access to the postulated intramicrosomal pool of nucleotide sugar.

Animals↗