'Like a shrivelled blood orange'--bilirubin, jaundice, and phototherapy.

The biochemistry of bilirubin is reviewed with particular reference to newborn infants. The formation, properties, and metabolism of bilirubin are summarized and the importance of molecular shape, hydrogen-bonding, and polarity on the biologic disposition of bilirubin is emphasized. The chemical basis for the subtle influence of visible (blue) light on bilirubin structure and metabolism is explained, and recent concepts of the mechanism of phototherapy are presented.

Light effects on transport and excretion of bilirubin in newborns.

There is now firm evidence that phototherapy has the following effects on bilirubin metabolism in humans with unconjugated hyperbilirubinemia. It rather rapidly converts a substantial fraction of the normal toxic 4Z, 15Z form of bilirubin to the 4Z, 15E form, which probably is less toxic. Simultaneously it enhances the overall excretion of bilirubin by converting it to oxidation products and structural and configurational isomers that are excretable in bile and urine without the need for glucuronidation.

Origin of mammalian biliprotein and rearrangement of bilirubin glucuronides in vivo in the rat.

In hepatobiliary disease bilirubin becomes bound covalently to serum albumin, producing a nondissociable bile pigment-protein complex (biliprotein). To elucidate the mechanism of biliprotein formation we studied the bile pigment composition of blood from animals with experimental cholestasis and carried out comparative studies on the rate of biliprotein formation in vivo and in vitro during incubation of bilirubin glucuronides with albumin. Bile duct ligation in the rat and guinea pig led to rapid accumulation in the circulation of bilirubin, heterogeneous bilirubin esters of glucuronic acid, and a biliprotein that migrated along with albumin on high performance liquid chromatography.

Phototherapy for neonatal jaundice: in vitro comparison of light sources.

Phototherapy results in the conversion of bilirubin to more water-soluble isomers. Six clinically used phototherapy lamps which differ in their emission spectra have been compared in their ability to produce configurational and structural isomers of bilirubin in vitro. For all of the lamps, the initial rate of configurational isomerization was highly correlated (r = 0.

Phototherapy for neonatal jaundice: optimal wavelengths of light.

Phototherapy results in transformation of bilirubin to more water-soluble isomers. The efficacy of monochromatic visible light from 350 to 550 nm in the fastest photoisomerization reaction was quantitated by high-pressure liquid chromatography. The most effective wavelengths in vitro (i.

A flow-cell method for measuring hepatic excretion of pigments continuously in rats.

The electronic absorption of effluent bile from restrained rats with indwelling bile cannulas can be measured directly and continuously in the wavelength region 430-800 nm using commercially available micro flow-cells. The method is useful for studying and characterizing the hepatic excretion of endogenous and exogenous pigments. Biliary excretion curves are obtained directly without requiring separate analyses of individual bile samples.

Reduction of biliverdin and placental transfer of bilirubin and biliverdin in the pregnant guinea pig.

Biliverdin was reduced to bilirubin in pregnant and foetal guinea pigs, and the 100000 g supernatant from homogenates of foetal liver, placenta and maternal liver showed high biliverdin reductase activity. The placental transport of unconjugated bilirubin and biliverdin was compared by injecting unlabelled and radiolabelled pigments into the foetal or maternal circulation and analysing blood collected from the opposite side of the placenta. Injected bilirubin crossed the placenta from foetus to mother and vice versa, but injected biliverdin did not appear to cross without prior reduction to bilirubin.

Hepatic excretion of circulating bilirubin photoproducts in the Gunn rat.

To investigate the origin and metabolism of the intermediates that occur in blood during phototherapy of neonatal jaundice, serum from irradiated homozygous Gunn rats was injected intravenously into other homozygous Gunn rats fitted with bile fistulas, and the excretion of pigment in the bile of the recipient rats was studied. In some experiments the donor rats were labeled with [14C]bilirubin; in others the recipient rats were labeled. Injection of donor serum from irradiated rats caused a transient burst of pigment excretion in the bile of the recipient rats.

Preparation and properties of crystalline biliverdin IX alpha. Simple methods for preparing isomerically homogeneous biliverdin and [14C[biliverdin by using 2,3-dichloro-5,6-dicyanobenzoquinone.

Amorphous isomerically pure biliverdin IX alpha is readily prepared in more than 70% yield by dehydrogenation of bilirubin with 2,3-dichloro-5,6-dicyanobenzoquinone in dimethyl sulphoxide under carefully controlled conditions. Crystalline biliverdin IX alpha and amorphous [14C]biliverdin can be obtained similarly in more than 40+ yield. The pure crystalline pigment was characterized by elemental analysis, methylation, chemical and enzymic reduction to bilirubin, i.

Blue light and bilirubin excretion.

Blue light converts bilirubin in the skin of jaundiced rats to metastable geometric isomers that are transported in blood and excreted in bile. The same reaction probably occurs in jaundiced babies exposed to light, particularly during treatment with phototherapy. Excretion of unisomerized bilirubin is prevented by intramolecular hydrogen bonding, and the pigment has to be metabolized to more polar derivatives to be excreted efficiently.

Photobilirubin: an early bilirubin photoproduct detected by absorbance difference spectroscopy.

Absorption of light converts bilirubin-IXalpha in solution to a mixture of what are probably cis-trans geometric isomers. This reaction is much faster than other photochemical reactions of bilirubin and reaches photoequilibrium before losses due to photooxidation are significant. At room temperature in the dark in the presence of trifluoroacetic acid or iodine or simply on standing, the photoproducts revert to the natural isomer.

Jaundice phototherapy: micro flow-cell photometry reveals rapid biliary response of Gunn rats to light.

Hepatic pigment clearance in rats can be followed continuously with photometric detectors designed for high-pressure liquid chromatography. This method showed that light has a fast effect on bilirubin metabolism in homozygous Gunn rats, even at low doses and intensities. This is consistent with geometric isomerization of bilirubin IXalpha as a primary step in phototherapy.