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Bilirubin photo-isomers: regiospecific acyl glucuronidation in vivo

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Abstract

(4Z,15Z)-Bilirubin-IXα, the end product of heme catabolism, requires uridine glucuronosyl transferase 1A1 (UGT1A1)-catalyzed glucuronidation for elimination in bile, where it appears as two isomeric monoglucuronides and a diglucuronide. When people are exposed to light, endogenous bilirubin is converted partly to photo-isomers that are produced in greater abundance during treatment of jaundiced babies with phototherapy. Little is known about the metabolism of the photo-isomers, other than that they appear not to require glucuronidation for elimination in bile. Studies have been hampered by their unavailability and instability, as well as confusion about the identity, structures, preparation, and purity of bilirubin photoproducts. This paper outlines methods for preparing photo-isomers of bilirubins in sufficient quantity and purity for metabolic studies in rats and reappraises the composition of some previous preparations. The studies show that (Z,E)-isomers of bilirubins and the structural isomer (Z)-lumirubin undergo glucuronidation in the rat, but unlike (4Z,15Z)-bilirubin, form only monoglucuronides. Moreover, glucuronidation is regiospecific for just one of the two propionic acid groups, the one attached to the isomerized half of the molecule. This unusual stereoselectivity appears to be dictated by intramolecular hydrogen bonding. Formation of hydroxylated bilirubins was not detected. During phototherapy, photo-isomers will compete with endogenous (4Z,15Z)-bilirubin for glucuronidation by nascent hepatic enzyme UGT1A1.

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Notes

  1. Lumirubin can be partially reconverted back to (4Z,15Z)-BR on irradiation with UV light or prolonged irradiation with blue light [13, 26], but its formation is irreversible on the time scale required to effect complete equilibration of (Z)-lumirubin and (E)-lumirubin. Thus, irradiation of (Z)-lumirubin with blue light leads rapidly to a photoequilibrium mixture of (Z)- and (E)-isomers, but not to a photoequilibrium mixture with (4Z,15Z)-BR which appears only along with overall pigment decomposition (McDonagh AF, unpublished observations). Therefore on the time scales of configurational isomerization and structural isomerization it is not inappropriate to describe lumirubin formation as irreversible.

  2. The nomenclature and identification of BR photoisomers in the literature is confusing. The photoisomer structures shown in Figs. 1 and 2 were established unambiguously by NMR and other spectroscopic and chemical methods published in 1982 and, for simplicity, the trivial name “lumirubin” (CAN 83664-21-5 and 83729-98-0) was assigned to structural isomers with the novel cycloheptadienyl ring (Fig. 2) [7, 8]. Previously the term “photobilirubin” had been used to describe early photoproducts of BR [22], but that term became redundant once the individual photoisomer chemical structures had been established. Yet the term was not completely abandoned, appearing in the literature as photobilirubins IA and IB, photoproducts isolated by Stoll et al. who thought them to be (4E,15Z) and (4Z,15E)-BR, respectively [13, 14]. However, as shown in this paper those structure assignments are incorrect. Another photoproduct, photobilirubin II, initially thought to contain two stable atropisomers of (4E,15E)-BR [13, 14] was subsequently assigned either the lumirubin structure (Fig. 2) or spiro-lactone structure (Fig. 3) [23], and finally the lumirubin structure [24]. The lumirubin structure in Fig. 2 is sometimes called (E,Z)-cyclobilirubin. Cyclobilirubin, originally called “unknown pigment”, was initially assigned the (4E,15E)-bilirubin structure [25], then the spiro-lactone structure [26], and eventually, in 1984 [27], the lumirubin structure elucidated earlier [7]. The name is confusing because it implies that a (Z,Z)-cyclobilirubin isomer could exist; however, such a structure is stereochemically impossible. In 1987, Bonnett and Ioannou published a table of structure/name correlations for the photoproducts isolated by different investigators [28]. Unfortunately, there are errors in that table. Adding further confusion, structures for several photoisomers and for bilirubin glucuronides depicted in a more recent review [29] are incorrect. The current paper uses unambiguous chemical nomenclature for configurational isomers and the trivial name lumirubin for isomers with a cycloheptadienyl ring system linking two adjacent pyrrolic rings formed by intramolecular cyclization of an endo vinyl group. There is no longer a need for the ambiguous and confusing photobilirubin or cyclobilirubin nomenclature.

  3. (P) = plus, (M) = minus define the helical sense of the molecular conformation and thus the chirality of the molecule, with reference to the relative orientation of the component two dipyrrinone chromophores and their long wavelength electric transition dipole moments lying along the long axis of each dipyrrinone [34].

  4. (Z)-Lumirubin has two stereogenic centers, denoted by *in Fig. 2. Prepared by irradiation of BR-HSA, (Z)-lumirubin is not identical to (Z)-lumirubin prepared by irradiation of BR in CHCl3/Et3N. Because of chiral induction by the protein the former is chiral and optically active whereas the latter is a racemate and optically inactive [49]. Both preparations behaved identically in the in vivo studies and are not distinguished in this paper.

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Acknowledgments

I thank Wilma Norona, Lucita A. Palma, and Andrew Phimister for technical assistance and the National Institutes of Health for partial financial support.

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Authors and Affiliations

  1. Department of Chemistry, University of Nevada, Reno, NV, 89557-0216, USA

    Antony F. McDonagh

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  1. Antony F. McDonagh
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Correspondence to Antony F. McDonagh.

Additional information

Antony F. McDonagh: deceased October 22, 2012.

Correspondence: David A. Lightner, Department of Chemistry, University of Nevada, Reno, Nevada 89557-0216, USA. e-mail: lightner@unr.edu.

Electronic supplementary material

Supplementary material comprises general materials and methods, hydrolysis of glucuronides in bile, alkaline methanolysis of lumirubin glucuronide, and radiochemical determination of lumirubin extinction coefficients.

Supplementary material 1 (DOC 43 kb)

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McDonagh, A.F. Bilirubin photo-isomers: regiospecific acyl glucuronidation in vivo. Monatsh Chem 145, 465–482 (2014). https://doi.org/10.1007/s00706-013-1076-6

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