Bilirubin Photooxidation Products in the Urine of Jaundiced Neonates Receiving Phototherapy

Lightner, David A.; Linnane, W. P.; Ahlfors, Charles E.

doi:10.1203/00006450-198408000-00003

Cited by 72 publications

(46 citation statements)

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“…The major treatment for jaundice in newborns, phototherapy, has sparked a large number of studies focused on the photophysics of bilirubin bound to HSA (41)(42)(43)(44)(45)(46)(47). In phototherapy, when infants are illuminated with light, bilirubin primarily bound to its high affinity HSA binding site is converted by light to more soluble nontoxic structural isomers that are easily eliminated from the circulatory system.…”

Section: Resultsmentioning

confidence: 99%

A Dynamic Model for Bilirubin Binding to Human Serum Albumin

Petersen¹,

Ha²,

Harohalli³

et al. 2000

Journal of Biological Chemistry

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Site-directed mutagenesis of human serum albumin was used to study the role of various amino acid residues in bilirubin binding. A comparison of thermodynamic, proteolytic, and x-ray crystallographic data from previous studies allowed a small number of amino acid residues in subdomain 2A to be selected as targets for substitution. The following recombinant human serum albumin species were synthesized in the yeast species Pichia pastoris: K195M, K199M, F211V, W214L, R218M, R222M, H242V, R257M, and wild type human serum albumin. The affinity of bilirubin was measured by two independent methods and found to be similar for all human serum albumin species. Examination of the absorption and circular dichroism spectra of bilirubin bound to its high affinity site revealed dramatic differences between the conformations of bilirubin bound to the above human serum albumin species. The absorption and circular dichroism spectra of bilirubin bound to the above human serum albumin species in aqueous solutions saturated with chloroform were also examined. The effect of certain amino acid substitutions on the conformation of bound bilirubin was altered by the addition of chloroform. In total, the present study suggests a dynamic, unusually flexible high affinity binding site for bilirubin on human serum albumin.The binding of bilirubin, a toxic metabolite of heme, to human serum albumin (HSA) 1 has been studied extensively for many years. Early medical interest in the bilirubin-HSA interaction arose when it became clear to physicians that prolonged high blood concentrations of bilirubin, which often occur in premature infants, could result in bilirubin encephalopathy (1-5). In this condition, significant amounts of bilirubin, which is toxic to all tissues, partitions from the blood to neuronal tissue causing irreversible brain damage. The prolonged high blood concentrations of bilirubin in premature infants results from underdevelopment of the liver, the organ responsible for conversion of bilirubin to a soluble form and its excretion into the bile. HSA binds bilirubin (K d ϭ 10 Ϫ7 -10 Ϫ8 M) at a high affinity site and acts as a buffer preventing the transfer of bilirubin from blood to the tissues, thus playing a critical role in impairing the development of bilirubin encephalopathy. In total, other studies on the pathology of bilirubin encephalopathy in premature infants have highlighted the importance of HSA as a bilirubin transport molecule in normal neonates (who experience a transient hyperbilirubinemia after birth) and in normal adults. These findings provided the motivation for many years of study on the bilirubin-HSA binding mechanism, making it one of the most studied of the HSA-ligand interactions (6 -11).Although some studies have suggested that lower affinity binding components (K d ϭ 10 Ϫ6 -10 Ϫ3 M) contribute to HSAbilirubin binding, most studies have primarily attempted to locate the high affinity binding site and to identify amino acid residues involved in the high affinity binding process. A number of studies th...

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Section: Resultsmentioning

confidence: 99%

A Dynamic Model for Bilirubin Binding to Human Serum Albumin

Petersen¹,

Ha²,

Harohalli³

et al. 2000

Journal of Biological Chemistry

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“…Configurational isomerization is reversible, whereas formation of lumirubins is irreversible ( Figure 1) (2). In addition, small amounts of oxidation products are formed (6).…”

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Bilirubin isomer distribution in jaundiced neonates during phototherapy with LED light centered at 497 nm (turquoise) vs. 459 nm (blue)

et al. 2016

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“…However, serial sampling at 15-20 min intervals for 180 min from 14 individual fetuses (91-139 days) showed that TSH was secreted in a markedly exaggerated pulsatile manner compared to that observed after birth. The mean amplitude of TSH pulses fell (p < 0.005) from 5.9 2 8.1 pU/ml in the fetuses to 2.1 + 1.1 pU/ml in five neonatal lambs (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) days) and to 1.5 f 0.4 pU/ml in three adult nonpregnant ewes. The mean pulse frequency for the 14 fetuses was 0.7 + 0.3 pulses/h and was reduced (p < 0.001) to 0.3 + 0.1 pulseslh in lambs and to 0.3 f 0.1 pulses/h in the ewes.…”

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confidence: 99%

Phototherapy for Neonatal Jaundice: in Vivo Clearance of Bilirubin Photoproducts

et al. 1985

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ABSTRACT. Phototherapy results in the conversion of native bilirubin to more water-soluble configurational and structural isomers. The serum half-life for the configurational isomer, the principal photoproduct in vivo, was determined by high pressure liquid chromatography in six premature infants following cessation of phototherapy. The mean half-life for this isomer was 15 h. The excretion of this isomer, calculated from the measured half-life, is less than half of daily bilirubin production, and therefore cannot account for the total bilirubin elimination observed during phototherapy. The serum concentration of the structural isomer, lumirubin, is lower than that of the configurational isomer; however, excretion is more rapid (serum half-life < 2 h). Because of its rapid excretion, lumirubin may be an important pathway for bilirubin elimination during phototherapy. (Pediatr Res 19: 205-208, 1985) Abbreviation HPLC, high pressure liquid chromatography Despite the widespread use of phototherapy in the treatment of neonatal hyperbilirubinemia (l), the detailed mechanism by which visible light affects bilirubin metabolism in jaundiced newborns is not known. The purpose of this study was to measure the rate of elimination of the principal bilirubin photoproduct, 4Z,15E-bilirubin, and to determine whether this is sufficient to Received June 22, 1984; accepted October 3, 1984. Address account for the decline in plasma bilirubin observed during phototherapy.Bilirubin, derived from the degradation of heme, is a potentially toxic, highly lipophylic molecule. In mammals this pigment is ravidlv cleared from the circulation and excreted as a ducuronide~onju~ate, primarily in the bile (2). Newborn i n f a k commonly develop hyperbilirubinemia due in part to a decreased ability to conjugate bilirubin and an increased pigment load. During vhototheravy, the most commonlv used treatment for unconj~~ated&~~dilirubinemia, bilirubin undergoes several reactions (3-7). All of these reactions yield photoproducts which are more polar and therefore presumably more easily excreted than native bilirubin. The fastest photochemical reaction is a Z to E isomerization reaction (5, 8) which in human infants yields primarily the 4Z,15E-bilirubin isomer (6). This reaction is readily reversible and up to 20% of the total bilirubin can be converted to this isomer during phototherapy (9-12).Since the quantum yield of the configurational isomerization reaction is at least 40 times greater than that for any other photochemical reaction of bilirubin (8), it has been assumed that the elimination of bilirubin during phototherapy is the result of formation and excretion of this photoproduct. We have used a rapid, quantitative HPLC method (5) to measure the half-life of the configurational isomer in serum of preterm infants undergoing phototherapy. We have found that the rate of elimination of the 4Z,15E-bilirubin isomer is much slower than previously reported (13) and cannot account for the decline in serum bilirubin observed in infants treated wit...

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Bilirubin Photooxidation Products in the Urine of Jaundiced Neonates Receiving Phototherapy

Cited by 72 publications

References 11 publications

A Dynamic Model for Bilirubin Binding to Human Serum Albumin

A Dynamic Model for Bilirubin Binding to Human Serum Albumin

Bilirubin isomer distribution in jaundiced neonates during phototherapy with LED light centered at 497 nm (turquoise) vs. 459 nm (blue)

Phototherapy for Neonatal Jaundice: in Vivo Clearance of Bilirubin Photoproducts

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