Review: Bilirubin pKa studies: new models and theories indicate high pKa values in water, dimethylformamide and DMSO.

School of Pharmacy, University of Wisconsin, Madison, 53705-2222, USA.
BMC Biochemistry (Impact Factor: 1.94). 03/2010; 11:16. DOI: 10.1186/1471-2091-11-16
Source: PubMed

ABSTRACT Correct aqueous pKa values of unconjugated bilirubin (UCB), a poorly-soluble, unstable substance, are essential for understanding its functions. Our prior solvent partition studies, of unlabeled and [14C] UCB, indicated pKa values above 8.0. These high values were attributed to effects of internal H-bonding in UCB. Many earlier and subsequent studies have reported lower pKa values, some even below 5.0, which are often used to describe the behavior of UCB. We here review 18 published studies that assessed aqueous pKa values of UCB, critically evaluating their methodologies in relation to essential preconditions for valid pKa measurements (short-duration experiments with purified UCB below saturation and accounting for self-association of UCB).
These re-assessments identified major deficiencies that invalidate the results of all but our partition studies. New theoretical modeling of UCB titrations shows remarkable, unexpected effects of self-association, yielding falsely low pKa estimates, and provides some rationalization of the titration anomalies. The titration behavior reported for a soluble thioether conjugate of UCB at high aqueous concentrations is shown to be highly anomalous. Theoretical re-interpretations of data in DMSO and dimethylformamide show that those indirectly-derived aqueous pKa values are unacceptable, and indicate new, high average pKa values for UCB in non-aqueous media (>11 in DMSO and, probably, >10 in dimethylformamide).
No reliable aqueous pKa values of UCB are available for comparison with our partition-derived results. A companion paper shows that only the high pKa values can explain the pH-dependence of UCB binding to phospholipids, cyclodextrins, and alkyl-glycoside and bile salt micelles.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The effect of polycationic polymers of polyacrylate guanidine (PAG) and polymethacrylate guanidine (PMAG) on bilirubin absorbance were studied in phosphate buffer (pH 7.4). It was shown that the change in absorbance spectra of bilirubin in the presence of PAG/PMAG can be associated with the formation of a bilirubin-polymer complex and dissociation of tetramers on bilirubin monomers. Also, the organic-inorganic composite materials based on silica gels and guanidine polymers were synthesized via the sol-gel technique. The incorporated guanidine polymers have a big influence on particle size distribution of silica gel due to their high cross-linking ability. The infrared spectroscopy revealed the presence of guanidine polymers inside solid networks of silica gel. The bilirubin adsorption process onto a guanidine functionalized silica surface was investigated. The Langmuir and Redlich-Peterson isotherm models were tested to explain the adsorption mechanism. The analysis of the adsorption isotherms confirms the possibility of electrostatic interactions of bilirubin molecules with guanidine polymers incorporated inside silica matrix. We conclude that cationic guanidine polymers might be effectively applied for bilirubin removal.
    Journal of Polymer Research 03/2014; 21(4). DOI:10.1007/s10965-014-0400-0 · 2.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Organic anion-transporting polypeptides or OATPs are central transporters in the disposition of drugs and other xenobiotics. In addition, they mediate transport of a wide variety of endogenous substrates. The critical role of OATPs in drug disposition has spurred research both in academia and in the pharmaceutical industry. Translational aspects with clinical questions are the focus in academia, while the pharmaceutical industry tries to define and understand the role these transporters play in pharmacotherapy. The present overview summarizes our knowledge on the interaction of food constituents with OATPs and on the OATP transport mechanisms. Further, it gives an update on the available information on the structure-function relationship of the OATPs and, finally, covers the transcriptional and posttranscriptional regulation of OATPs.
    Current Topics in Membranes 01/2014; 73:205-32. DOI:10.1016/B978-0-12-800223-0.00005-0 · 1.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this study, vibrational circular dichroism (VCD) spectroscopy was employed for the first time to study the bilirubin (BR) interaction with model membranes and models for membrane proteins. An enantioselective interaction of BR with zwitterionic 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and sphingomyelin (SPM) liposomes was observed by VCD and electronic circular dichroism (ECD) complemented by absorption and fluorescence spectroscopy. The M-form of BR was preferentially recognized in the BR/DMPC system at concentration above 1×10(-4)M, for lower concentrations the P-form of BR was recognized by the DMPC liposomes. The VCD spectra also showed that the SPM liposomes, which represent the main component of nerve cell membrane, were significantly more disturbed by the presence of BR than the DMPC liposomes - a stable association with a strong VCD signal was observed providing the explanations for the supposed BR neurotoxicity. The effect of time and pH on the BR/DMPC or SPM liposome systems was shown to be essential while the effect of temperature in the range of 15-70°C was negligible demonstrating the surprisingly high temperature stability of BR when interacting with the studied membranes. The influence of a membrane protein was tested on a model consisting of poly-l-arginine (PLAG) bound in the α-helical form to the surface of 1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) liposomes and sodium dodecyl sulfate micelles. VCD and also ECD spectra showed that a variety of BR diastereoisomers interacted with PLAG in such systems. In a system of PLAG with micelles composed of sodium dodecyl sulfate, the M-form of bound BR was observed.
    Biochimica et Biophysica Acta 12/2013; 1838(3). DOI:10.1016/j.bbamem.2013.12.005 · 4.66 Impact Factor

Full-text (2 Sources)

Available from
Jun 4, 2014