Bilirubin, binding to albumin

Fig. 7.10 Matching of RR from 7 a (thick lines) with the extended form of bilirubin IX (dashed lines). The extended conformation of bilirubin is one of several possibilities and it is uncertain which of these it adopts when binding to albumin. The iron atom of 7a is placed at the central methylene of bilirubin. A number of the peripheral groups have been omitted from the structures for clarity. Reproduced with permission from R. B. Lauffer, A. C. Vincent, S. Padmanabhan and T. I. Meade, J. Amer. Chem. Soc. 109, 2216 (1987). (1987) American Chemical Society.

For further degradation, bilirubin is transported to the liver via the blood. As bilirubin is poorly soluble, it is bound to albumin for transport. Some drugs that also bind to albumin can lead to an increase in free bilirubin. 

Albumin is the most abundant protein in human and other animal plasma. It is estimated that up to 40% of the total albumin in humans is in circulation transporting essential nutrients, especially those that are sparingly soluble in aqueous-based plasma. For example, the fatty acids, which are important fuel molecules for the peripheral tissue, are distributed by albumin. In addition, albumin is the plasma transport protein for other substances including bilirubin, thyroxine, and steroid hormones. Also, many drugs including aspirin, sulfanilamides, clofibrate, and digitalis bind to albumin and are most likely carried to their sites of action by the protein. 

N6. Novak, M., Polacek, K., and Melichar, V., Competition between bilirubin and non-esterified fatty acids for binding to albumin. Biol. Neonatorum 4, 310-315 (1962). 

Both conjugated bilirubin and unconjugated bilirubin may be present in plasma. Conjugated bilirubin is water. soluble. Unconjugated bilirubin is not water soluble and binds to albumin from which it may be transferred to other proteins such as those in cell membranes. It is neurotoxic, and if levels rise too high in neonates, permanent brain damage can occur. 

After the reduction of biliverdin, the bilirubin that is formed then undergoes a series of transport and transformation steps which ultimately lead to its excretion in the intestinal tract. From the sites of its production, bilirubin is released into the plasma where it efficiently binds to albumin, which acts as a plasma-transport system. The bilirubin-albumin complex is carried in the plasma to liver cells (hepatocytes), where the bilirubin is released from its albumin carrier protein and transported across the cell bilayer membrane into the hepatocyte. Once inside, the bilirubin is bound in the cytoplasm to anion-binding proteins such as ligandin. The latter carries the bilirubin to membrane-bound enzymes (localised in the endoplasmic reticulum of the liver cell) which catalyse the esterification of bilirubin, the ester groups (mainly p-D-glucuronoside, but also smaller amounts of fi-D-xylo-pyranosides and p-D-glucopyranosides) being transferred from their uridine diphosphate nucleotides. 

BNIrubm (which Is hydrophobic) binds to albumin In the plasma and Is t-ransport-ed to the llvar. Here llgandin serves as tha Intracellular transporter and carries bilirubin to tha endoplasmic reticulum where It Is made hydrophilic by conjugation with UPP-glucuronate... 

Some Conjugated Bilirubin Can Bind Covalently to Albumin... 

When levels of conjugated bilirubin remain high in plasma, a fraction can bind covalently to albumin (delta bilirubin). Because it is bound covalently to albumin, this fraction has a longer half-life in plasma than does conventional conjugated bilirubin. Thus, it remains elevated during the recovery phase of obstructive jaundice after the remainder of the conjugated bilirubin has declined to normal levels this explains why some patients continue to appear jaundiced after conjugated bilirubin levels have returned to normal. 

Another important function of albumin is its ability to bind various ligands. These include free fatty acids (FFA), calcium, certain steroid hormones, bilirubin, and some of the plasma tryptophan. In addition, albumin appears to play an important role in transport of copper in the human body (see below). A vatiety of drugs, including sulfonamides, penicilhn G, dicumarol, and aspirin, are bound to albumin this finding has important pharmacologic implications. 

Bilirubin derives largely from senescent erythrocyte hemoglobin [for reviews, see references (F9, G7, L6, S3, Wll)]. When transported in plasma the pigment is bound to albumin (B9, 04). Dissociation from albumin precedes rapid uptake by liver tissues (B4, Bll, B29). This uptake and the transfer of bilirubin to its sites of metabolism may be mediated by cytoplasmic binding proteins (G8, Gll, L8, M9). 

At a bilirubin albumin molecular ratio below one the added binding protein will thus act as a kind of buffer, keeping the concentration of unbound substrate sufficiently low to inhibit colloid formation (B25) or precipitation onto bound bilirubin (B26), and will prevent aspecific binding to cell particulates. The binding protein can also be thought of as a reservoir providing a continuous stream of molecularly dispersed sub-... 

Z Uptake of bilirubin by the liven Bilirubin is only slightly soluble in plasma and, therefore, is transported to the liver by binding non-covalently to albumin. [Note Certain anionic drugs, such as salicylates and sulfonamides,1 can displace bilirubin from abu-min, permitting bilirubin to enter the central nervous system (CNS). This causes the potential for neural damage in infants.] Bilirubin dissociates from the carrier albumin molecule and enters a hepatocyte, where it binds to intracellular proteins, particularly the protein ligandin. 

Electrophoretic studies (G2, M2) have shown that both types of bilirubin are bound to albumin and sometimes a-globulin. Klatskin and Bungards (K6) found that this binding occurs between pH 6 and pH 9 and that below pH 5 separation occurs almost completely with respect to bilirubin but only partially with the conjugated pigment. This suggests that bilirubin and conjugated bilirubin are attached in different ways to plasma proteins. 

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