Phototherapy for neonatal jaundice. Configurational isomers of bilirubin

McDonagh, Antony F.; Palma, Lucita A.; Trull, Francesc R.; Lightner, David A.

doi:10.1021/ja00388a103

Cited by 144 publications

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“…The hypothesis was subsequentl y tested (15) and confirmed in Gunn rats (12,24). More recently, the structures of the Eisomers have been proved, and it has been shown that these isomers are formed in jaundiced rats exposed to blue light and in humans during phototherapy (14,16). At present, current evidence favors the photochemical configurational isomerization of VCB (to E-isomers) as one of the most rapidly occurring photochemical events in phototherapy.…”

Section: Discussionmentioning

confidence: 94%

Bilirubin Photooxidation Products in the Urine of Jaundiced Neonates Receiving Phototherapy

1984

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SummaryBilirubin-IXa photooxidation products were detected by high performance liquid chromatography in the urine of neonates undergoing phototherapy for hyperbilirubinemia. The in vivo photoproducts were identified by chromatographic comparison with authentic synthetic standards using two complementary methods. Bilirubin photooxidation products were not detected in urine from jaundiced infants not receiving phototherapy. The specific photoproducts identified in the urine include propentdyopents, hematinic acid imide and its hydrolysis product (3-carboxy-2-methyl-2-hexenedioic acid), and the hydrolysis product (2-vinyl-3-methyl-maleic acid) of methylvinylmaleimide. Their total urinary concentrations were low (0.2-0.9 mg/dl) during phototherapy. These observations show that photooxidation of bilirubin clearly does occur during phototherapy. They are consistent with the view that, although photooxidation is not the major photochemical event associated with phototherapy, it can and clearly does occur concurrently with photoisomerization.

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Section: Discussionmentioning

confidence: 94%

Bilirubin Photooxidation Products in the Urine of Jaundiced Neonates Receiving Phototherapy

1984

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“…Photooxidation may also occur (5,6). Due to increased polarity, these isomers can be excreted in bile and urine, bypassing the need for conjugation.…”

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confidence: 99%

Early formation of bilirubin isomers during phototherapy for neonatal jaundice: effects of single vs. double fluorescent lamps vs. photodiodes

et al. 2015

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Background:In neonatal jaundice, phototherapy converts bilirubin to more polar photoisomers which can be excreted without conjugation. We measured changes in the concentration of bilirubin Z,E-photoisomer during the first 4 h of intensive phototherapy using single fluorescent lights as a reference, compared to double fluorescent lights, and a single unit of photodiodes. Methods: Neonates (N = 42; birth weight: 1,200-4,690 g; gestational age: 28-42 wk) were studied during phototherapy. Infants were randomized to: (i) single, or (ii) double fluorescent phototherapy; or (iii) single unit photodiodes. Irradiance was measured. Serum bilirubin (by cooximetry) and Z,E bilirubin (by high-pressure liquid chromatography) were measured at 0,15, 30, 60, 120, and 240 min after the start of phototherapy. Data were analyzed with a linear mixed model. results: There was a highly significant increase of Z,E-bilirubin over time (P < 0.0001), starting at 15 min. Photoisomers reached ~25% of total bilirubin concentration after 4 h. However, there were no significant differences between the three randomized groups in spite of significantly higher irradiance using double fluorescent lights vs. single fluorescent or photodiodes. conclusion: Formation of bilirubin photoisomers is rapid, and occurs early during intensive phototherapy for neonatal jaundice. The rate and level of photoisomerization was not influenced by irradiance and light source. P hototherapy is the standard treatment for hyperbilirubinemia in newborns, and is administered to prevent kernicterus and other sequelae of bilirubin neurotoxicity (1).It is effective and considered safe. However, a recent report suggests that "aggressive" phototherapy in the smallest infants of birth weight 501-750 g may be associated with increased risk of death (2).When native bilirubin IXα (Z,Z) in neonates is exposed to light, a rapid photochemical reaction produces water-soluble configurational (4Z,15E; 4E,15Z; 4E,15E) and structural (Z-lumirubin; E-lumirubin) isomers (3,4). Photooxidation may also occur (5,6). Due to increased polarity, these isomers can be excreted in bile and urine, bypassing the need for conjugation. It has recently been suggested that these isomers, because of their polarity, should be less able to cross the bloodbrain barrier (1,7). If this is correct, photoisomer formation might be directly neuroprotective, irrespective of the effect on excretion. Experimental data suggest that bilirubin photoisomers are less toxic than the native IX α (Z,Z), but there are methodological weaknesses in these studies (1). Thus, experimental proof of the hypothesized direct neuroprotective effects of photoisomerization is still needed. Both different light qualities and variable light irradiance are commonly employed in practical phototherapy. Herein we have investigated whether such factors may impact on photoisomer formation.The common light sources used in phototherapy are either fluorescent, or tungsten-halogen lamps with wide emission spectrum, or light-emitting diodes (LEDs) wi...

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“…Although the photoproducts were not characterized further, there is little doubt that the major new peak is the E,Z isomer of 7 (Fig. 7) and the minor peak the E,E isomer McDonagh et al, 1979;McDonagh et al, 1982). When the serum solution was injected i.v.…”

Section: Resultsmentioning

confidence: 99%

Slipping Past UGT1A1 and Multidrug Resistance-Associated Protein 2 in the Liver: Effects of Steric Compression and Hydrogen Bonding on the Hepatobiliary Elimination of Synthetic Bilirubins

McDonagh

Boiadjiev²,

Lightner³

2008

Drug Metab Dispos

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ABSTRACT:The hepatobiliary metabolism and excretion of three isomeric bilirubin analogs with propanoic replaced by benzoic acid side-chains were studied in the rat. Despite their isomeric relationship and similar constitutions, the three analogs were metabolized quite differently from each other and from bilirubin. In the di-o-benzoic compound, steric hindrance involving the phenyl groups reinforces intramolecular hydrogen bonding of the two carboxyl groups. This compound is considerably less polar than bilirubin on reversephase high-performance liquid chromatography and, like bilirubin, was not excreted in bile in UGT1-deficient (Gunn) rats. But, quite unlike bilirubin, it was not glucuronidated or excreted in bile in normal rats. In contrast to both bilirubin and the di-o-benzoic isomer, the more polar m-and p-isomers, in which intramolecular hydrogen bonding of carboxyl groups is sterically difficult, were excreted rapidly in bile in unchanged form in both normal and Gunn rats. However, only one of them, the di-m-isomer, was excreted rapidly and unchanged in bile in rats (TR ؊ rats) congenitally deficient in the canalicular ATP-binding cassette transporter Mrp2. The marked differences in hepatobiliary metabolism of the three isomers studied can be rationalized on the basis of their computed three-dimensional structures and minimum-energy conformations and the remote effects of steric compression on intramolecular hydrogen bonding.Bilirubin (1) (Fig. 1) is formed in mammals by reduction of biliverdin (2), end product of most heme catabolism. It is insoluble in water, lipophilic, extensively protein-bound in plasma, and, unlike biliverdin, requires phase-2 metabolism, mainly to mono-and diglucuronides, for elimination. Once used as a liver function test (Harrop and Barron, 1931;Kornberg, 1942), bilirubin is a constituent of several Asian traditional medicines (McDonagh, 1990), and its antioxidant/anti-inflammatory properties are currently attracting attention (Stocker et al., 1987;Stocker, 2004; Ollinger et al., 2007a,b). Historically, bilirubins have been useful for investigating mechanisms of acyl glucuronidation, membrane transport, and hepatobiliary excretion. Bilirubin and its two monoglucuronides are isozyme-specific substrates for the glucuronosyl transferase UGT1A1 (Owens et al., 2005), and its three acyl glucuronides are classic examples of compounds that depend wholly on the ATP-binding cassette transporter MRP2 (ABCC2) for elimination in bile (Nies and Keppler, 2007). Deficiencies of UGT1A1 cause neonatal jaundice, Gilbert's and CriglerNajjar syndromes (Kaplan and Hammerman, 2005), and congenital deficiency of MRP2 underlies the rare Dubin-Johnson syndrome (Nies and Keppler, 2007). Studies on bilirubin glucuronides led to the discovery that acyl glucuronides of many drugs are reactive, potentially toxic, metabolites (Smith et al., 1986), and studies on bilirubin analogs have revealed how subtle changes in molecular conformation can profoundly influence hepatic metabolism (McDonagh and Lightner, 1991;...

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Phototherapy for neonatal jaundice. Configurational isomers of bilirubin

Cited by 144 publications

References 0 publications

Bilirubin Photooxidation Products in the Urine of Jaundiced Neonates Receiving Phototherapy

Bilirubin Photooxidation Products in the Urine of Jaundiced Neonates Receiving Phototherapy

Early formation of bilirubin isomers during phototherapy for neonatal jaundice: effects of single vs. double fluorescent lamps vs. photodiodes

Slipping Past UGT1A1 and Multidrug Resistance-Associated Protein 2 in the Liver: Effects of Steric Compression and Hydrogen Bonding on the Hepatobiliary Elimination of Synthetic Bilirubins

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