The pathochemistry of kernicterus.
The stoichiometry of bilirubin--albumin interaction has been analyzed and quantitated in several recent studies, confirming that albumin binding of bilirubin obeys the law of mass action [4, 5, 14, 16, 26, 36, 43, 46, 61, 65, 73, 92, 111]. These studies provide a basis for interpreting bilirubin transport, cell uptake and toxicity from physicochemical and pharmacologic perspectives [35, 42, 58, 59]. In this report, we propose a model of the pathogenesis of kernicterus which views serum albumin and tissue as competing with each other for binding the miscible bilirubin pool. Evidence is presented to show that bilirubin normally binds reversibly to cellular membranes and certain soluble enzymes just as it does to albumin; the unbound bilirubin concentration is the driving force for both albumin and tissue binding. We propose that albumin binding is determined by the concentration of free bilirubin anion (which is essentially unaffected by physiologic pH changes), and that tissue binding is mainly determined by the concentration of free bilirubin acid (which is greatly influenced by pH). When bilirubin--tissue complexes are formed, essential cell functions may be inhibited, producing cellular acidosis, irreversible intracellular aggregation of bilirubin, and cell death. In developing this argument, we will sequentially discuss relevant features of bilirubin chemistry, the binding of bilirubin to albumin, the formation of bilirubin--tissue complexes, bilirubin toxicity, alternative viewpoints of bilirubin transport, and, finally, the implications of this model to the clinical management of jaundiced infants. It should be emphasized that this paper is an attempt to analyze bilirubin transport and toxicity using basic chemical principles; it is an extension of previously published proposals [17, 77], and will undoubtedly require further modification as additional experimental data becomes available.
D001663:Bilirubin / Q000097:blood* / Q000494:pharmacology; D001667:Binding, Competitive; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D005078:Exchange Transfusion, Whole Blood; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000628:therapy; D007647:Kernicterus / Q000097:blood* / Q000517:prevention & control; D008954:Models, Biological; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D012995:Solubility
D012709:Serum Albumin; D001663:Bilirubin