The effect of hematocrit on the efficacy of phototherapy for neonatal jaundice.

Background: The therapeutic phototherapy action spectrum ranges from 420 to 500 nm. However, a recent report of improved efficacy of fluorescent "turquoise" light (~490 nm) as compared with blue light (~450 nm) underscores the need to define an optimal action spectrum for precision-targeted phototherapy using very narrow wavelength ranges.

Methods: We used a current semi-empirical model of the optical properties of skin for robust calculations of the fraction of light absorbed by bilirubin at various wavelengths that could be confounded by hemoglobin (Hb), melanin, and skin thickness.

Bilirubin, copper-porphyrins, and the bronze-baby syndrome.

Controlled in vitro spectroscopic measurements reveal that bilirubin does not photosensitize the degradation of copper-porphyrins, as has been proposed for the mechanism of the bronze-baby syndrome, an uncommon side-effect of phototherapy. Calculations also show that copper-porphyrins are unlikely to cause the "bronzing." In conclusion, the copper-porphyrin hypothesis is photochemically implausible.

The biliverdin-bilirubin antioxidant cycle of cellular protection: Missing a wheel?

Bilirubin reportedly protects cultured cells from the toxicity of a 10,000-fold molar excess of H(2)O(2). A bilirubin-biliverdin cycling mechanism has been proposed to explain this remarkable effect whereby bilirubin reacts with oxyradicals specifically generating biliverdin, which is then reduced back to bilirubin by NADPH/biliverdin reductase. Chemical evidence for this mechanism was formation of biliverdin during incubation of bilirubin-albumin with 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH) in vitro and the assumption that biliverdin was formed by the reaction of peroxyl radicals with bilirubin.

Early isomerization of bilirubin in phototherapy of neonatal jaundice.

Neonatal jaundice is usually treated with phototherapy that converts bilirubin to more polar stereoisomers. These should theoretically be less able to cross the blood-brain barrier. The rates of photoisomer formation and concentrations accumulating in the circulation may have a bearing on the risk of kernicterus.

Controversies in bilirubin biochemistry and their clinical relevance.

Despite a century of research, several clinically relevant areas of bilirubin biochemistry remain controversial, poorly understood, or unrecognized. These include: (i) The structure and molecularity of bilirubin under physiological environments such as membranes, brain tissue and when bound to proteins. Related to this is the large number of structurally different bilirubin species that may occur in blood under pathological conditions and their potential effects on measurements of bilirubin and free bilirubin.

Metabolism of haem in Caco-2 cells.

The haem oxygenase-1-biliverdin reductase system degrades haem and generates biliverdin and bilirubin, both of which possess antioxidant and anti-inflammatory properties. Biliverdin and bilirubin are protective in intestinal injury models, but little is known about their generation and fate in the intestine. In the present work, an in vitro intestinal epithelial cell model, Caco-2 cells, were exposed to haem from either the apical or the basolateral side, and bile pigment generation and transport were measured spectrophotometrically and with high-pressure liquid chromatography.

Photoisomers: obfuscating factors in clinical peroxidase measurements of unbound bilirubin?

Objectives: The objectives of the study were to measure the effect of 4Z,15E-bilirubin on peroxidase free bilirubin measurements and to review the literature on this topic.

Methods: 4Z,15E-Bilirubin was generated in situ in serum or serum albumin solution through controlled irradiation of isomerically pure 4Z,15Z-bilirubin IXalpha, under conditions in which the total amount of bilirubin remained constant. Reactions were monitored by difference spectroscopy, to ensure that solutions were not irradiated beyond the initial photostationary state and that concentrations of other isomers were kept to a minimum.

Crystallographic analysis of human serum albumin complexed with 4Z,15E-bilirubin-IXalpha.

Bilirubin, an insoluble yellow-orange pigment derived from heme catabolism, accumulates to toxic levels in individuals with impaired or immature liver function. The resulting jaundice may be managed with phototherapy to isomerize the biosynthetic 4Z,15Z-bilirubin-IXalpha to more soluble and excretable isomers, such as 4Z,15E-bilirubin. Bilirubin and its configurational isomers are transported to the liver by human serum albumin (HSA) but their precise binding location(s) on the protein have yet to be determined.

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.

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.

Targeted inhibition of glucuronidation markedly improves drug efficacy in mice - a model.

Finding UDP-glucuronosyltransferases (UGT) require protein kinase C-mediated phosphorylation is important information that allows manipulation of this critical system. UGTs glucuronidate numerous aromatic-like chemicals derived from metabolites, diet, environment and, inadvertently, therapeutics to reduce toxicities. As UGTs are inactivated by downregulating PKCs with reversibly-acting dietary curcumin, we determined the impact of gastro-intestinal glucuronidation on free-drug uptake and efficacy using immunosuppressant, mycophenolic acid (MPA), in mice.

Influence of conformation and intramolecular hydrogen bonding on the acyl glucuronidation and biliary excretion of acetylenic bis-dipyrrinones related to bilirubin.

Glucuronidation and transporter-mediated efflux into bile are important in the elimination of xeno- and endobiotics, including the natural biladienone pigment bilirubin. The mechanisms of these processes and the structural factors that dictate whether cholephilic compounds are excreted directly in bile or require prior glucuronidation are poorly understood. To investigate effects of molecular shape and intramolecular hydrogen bonding on the interplay between direct excretion and glucuronidation in the liver, we studied a series of novel synthetic exploded and homologated bilirubin analogues.

Ex uno plures: the concealed complexity of bilirubin species in neonatal blood samples.

Blood from jaundiced neonates often contains several isomers of bilirubin in addition to the biosynthetic isomer that causes kernicterus. These isomers are generated during phototherapy or during normal exposure of infants to ambient light. Their presence is generally overlooked or ignored in clinical measurements of circulating bilirubin concentrations and the interpretation of these values.

Synthesis and hepatic transport of strongly fluorescent cholephilic dipyrrinones.

A new class of highly fluorescent (phi(F) 0.3-0.8) low molecular weight water-soluble cholephilic compounds has been synthesized in two steps from dipyrrinones.

Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector.

Crigler-Najjar syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by a deficiency of uridine diphospho-glucuronosyl transferase 1A1. Current therapy relies on phototherapy to prevent kernicterus, but liver transplantation presently is the only permanent cure. Gene therapy is a potential alternative, and recent work has shown that helper-dependent adenoviral (HD-Ad) vectors, devoid of all viral coding sequences, induce prolonged transgene expression and exhibit significantly less chronic toxicity than early-generation Ad vectors.