Ionization and self-association of unconjugated bilirubin, determined by rapid solvent partition from chloroform, with further studies of bilirubin solubility.

Hahm, Joon-Soo; Ostrow, J. Donald; Mukerjee, Pasupati; Celic, Lillian

doi:10.1016/s0022-2275(20)40764-3

Cited by 95 publications

(54 citation statements)

References 49 publications

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“…The predominant physiologic isomer, bilirubin IX ␣ , is maintained in a ridge-tile conformation by intramolecular hydrogen bonding between the two carboxylic acid groups and the opposing dipyrromethenone moieties. Bilirubin is unusual in that it exhibits limited aqueous solubility at physiologic pH (2) and yet also is poorly soluble in apolar solvents (3). The physical characteristics of the bilirubin molecule that result in its distinctive solubility may have important physiological ramifications.…”

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confidence: 99%

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Localization of bilirubin in phospholipid bilayers by parallax analysis of fluorescence quenching

Zucker

Goessling

Bootle

et al. 2001

Journal of Lipid Research

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It has been proposed that the neurotoxicity observed in severely jaundiced infants results from the binding of unconjugated bilirubin to nerve cell membranes. However, despite potentially important clinical ramifications, there remains significant controversy regarding the physical nature of bilirubin-membrane interactions. We used the technique of parallax analysis of fluorescence quenching (Chattopadhyay, A., and E. London. 1987. Biochemistry. 26: 39-45) to measure the depth of penetration of bilirubin in model phospholipid bilayers. The localization of unconjugated bilirubin and ditaurobilirubin within small unilamellar vesicles composed of dioleoylphosphatidylcholine was determined through an analysis of the quenching of bilirubin fluorescence by spin-labeled phospholipids, and by bilirubin-mediated quenching of a series of anthroyloxy fatty acid probes at various depths within the membrane bilayer. Findings were further verified with potassium iodide as an aqueous quencher. Our results indicate that, at pH 10, unconjugated bilirubin localizes approximately 20 Å from the bilayer center, in the region of the polar head groups. Further analyses suggest a modest influence of pH, membrane cholesterol content, and vesicle diameter on the bilirubin penetration depth. Taken together, these data support that, under physiologic conditions, bilirubin localizes to the polar region of phospholipid bilayers, near the membrane-water interface. -Zucker, S. D., W. Goessling, E. J. Bootle, and C. Sterritt. Localization of bilirubin in phospholipid bilayers by parallax analysis of fluorescence quenching.

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“…32: 427A). 2 To whom correspondence should be addressed. e-mail: zuckersd@email.uc.edu originally described by Chattopadhyay and London (22), to more precisely define the location of bilirubin within model phospholipid bilayers.…”

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confidence: 99%

Localization of bilirubin in phospholipid bilayers by parallax analysis of fluorescence quenching

Zucker

Goessling

Bootle

et al. 2001

Journal of Lipid Research

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“…Indeed, p K a values ranging from 4.4 to 9.3 (for review see 17 ) have been described in the literature. Since most of the carboxylic acid p K a values are around 5, and values above 6 are seldom encountered 18 , 19 , higher p K a values reported in some studies suggest the remarkable effect of intramolecular hydrogen bonding on proton dissociation 4 , 5 , 20 . Thus, it is not surprising that when using solvents that break the internal hydrogen bonds (such as dimethyl sulfoxide), very low and identical p K a values of 4.4 for both carboxyl groups were found 21 .…”

Section: Discussionmentioning

confidence: 95%

“…Potentiometric titration of bilirubin dianion salt in simple aqueous solution led to progressive precipitation of insoluble bilirubin diacid as the pH fell below about 8.0 20 , 23 . It has been suggested that the aqueous titration curves could be reconstructed by using the p K a values obtained in dimethyl formamide or dimethyl sulfoxide, and applying a mathematical model that assumes that bilirubin is only solubilized by prior ionization of the solid bilirubin diacid.…”

Section: Discussionmentioning

confidence: 99%

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Physico-chemical characterization of bilirubin-10-sulfonate and comparison of its acid–base behavior with unconjugated bilirubin

Čepa

Dejmková

Lešetický

et al. 2021

Sci Rep

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Unconjugated bilirubin (UCB) is the end-product of heme catabolism in the intravascular compartment. Although beneficial for human health when mildly elevated in the body, when present at greater than a critical threshold concentration, UCB exerts toxic effects that are related to its physico-chemical properties, particularly affecting the central nervous system. The aim of the present study was to characterize bilirubin-10-sulfonate (ranarubin), a naturally occurring bile pigment, including determination of its mixed acidity constants (pKa*). Thanks to the presence of the sulfonic acid moiety, this compound is more polar compared to UCB, which might theoretically solve the problem with an accurate determination of the UCB pKa* values of its propionic acid carboxylic groups. Bilirubin-10-sulfonate was synthesized by modification of a previously described procedure; and its properties were studied by mass spectrometry (MS), nuclear magnetic resonance (NMR), infrared (IR), and circular dichroism (CD) spectroscopy. Determination of pKa* values of bilirubin-10-sulfonate and UCB was performed by capillary electrophoresis with low pigment concentrations in polar buffers. The identity of the synthesized bilirubin-10-sulfonate was confirmed by MS, and the pigment was further characterized by NMR, IR, and CD spectroscopy. The pKa values of carboxylic acid moieties of bilirubin-10-sulfonate were determined to be 5.02, whereas those of UCB were determined to be 9.01. The physico-chemical properties of bilirubin-10-sulfonate were partially characterized with low pKa* values compared to those of UCB, indicating that bilirubin-10-sulfonate cannot be used as a surrogate pigment for UCB chemical studies. In addition, using a different methodological approach, the pKa* values of UCB were found to be in a mildly alkaline region, confirming the conclusions of a recent critical re-evaluation of this specific issue.

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Bilirubin Metabolism and Jaundice

Wolkoff

Berk

2017

Schiff's Diseases of the Liver

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Ionization and self-association of unconjugated bilirubin, determined by rapid solvent partition from chloroform, with further studies of bilirubin solubility.

Cited by 95 publications

References 49 publications

Localization of bilirubin in phospholipid bilayers by parallax analysis of fluorescence quenching

Localization of bilirubin in phospholipid bilayers by parallax analysis of fluorescence quenching

Physico-chemical characterization of bilirubin-10-sulfonate and comparison of its acid–base behavior with unconjugated bilirubin

Bilirubin Metabolism and Jaundice

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