Transport of Bilirubin

Bilirubin formed in extrahepatic tissues is transported to the liver for excretion in bile. Since bilirubin is virtually insoluble in aqueous media, it is transported to the liver bound noncovalently to serum albumin. The bilirubin-albumin complex increases the amount of bilirubin carried 

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B14. Billing, B. H., Williams, R., and Richards, T. G., Defects in hepatic transport of bilirubin in congenital hyperbilirubinaemia an analysis of plasma bilirubin disappearance curves. Clin. Sci. 27, 245-257 (1964). 

The hepatic transport of bilirubin from plasma to bile involves three independent, but related mechanisms, i.e., uptake, conjugation, and... 

The bilirubin that is produced in phagocytic cells from degradation of hemoglobin represents the majority of the bilirubin that is produced and must be eliminated. This initially requires transport of bilirubin from the phagocytic cells to the liver. Normally, bilirubin is secreted from phagocytic cells and complexed with albumin for transport to the liver. It is essential that bilirubin is transported through the circulation bound to albumin. The toxicity of... 

Jaundice does not necessarily accompany cholestasis. In severe and prolonged cholestasis, particularly if obstructive, jaundice is generally always in evidence. In cholestasis, the third fraction, known as delta bilirubin, can largely be detected by means of the diazo method. This fraction is firmly bound to albumin and can therefore only be dissociated and excreted slowly. For this reason, jaundice occurring together with cholestasis tends to subside at a significantly slower rate than the increased bile acid level in the serum. In this case, jaundice is due to a reflux of bilirubin from the canaliculus into the blood or a bidirectional transport of bilirubin via the sinusoidal membrane. Sometimes jaundice is caused by metabolic dysfunction of the liver cells. Bilirubin also acts as an antioxidant. 

Hepatocytes take up bilirubin from the sinusoidal plasma and excrete it after conjugation with glucuronic acid across the canalicular membrane into the bile. The entry and exit steps and the transport of bilirubin within the cell are not completely understood. The following is a plausible interpretation of the available data. 

B21a. Billing, B. H., Maggiore, Q. S., and Goulis, G., The action of cholecystographic contrast media and novobiocin on the hepatic transport of bilirubin. In The Biliary System (W. Taylor, ed.), pp. 215-223. Blackwell, Oxford, 1966. 

The hepatocytes are the most active sites of protein synthesis, and albumin plays important roles in the transport of bilirubin, anions, fatty acids, several hormones, and xenobiotics. Albumin also is important in determining the colloidal osmotic pressure of plasma and other body fluids. Other proteins synthesized in the liver include the acute-phase response proteins, complement proteins, and the coagulation cascade proteins (see Chapter 8). The levels of plasma proteins reflect the balance between the rates of synthesis, utilization, and degradation. The liver also plays an important role in the metabolism of cholesterol and lipoproteins (see Chapter 9). 

Bilirubin formed in peripheral tissues is transported to the hver by plasma albumin. The further metabolism of bihtubin occuts primarily in the hver. It can be divided into thtee processes (1) uptake of bilirubin by hver parenchymal cells, (2) conjugation of bilirubin with glucuronate in the endoplasmic reticulum, and (3) secretion of conjugated bilirubin into the bile. Each of these processes will be considered separately. 

In the liver, the bilirubin is removed from albumin and taken up at the sinusoidal surface of the hepato-cytes by a carrier-mediated saturable system. This facilitated transport system has a very large capacity, so that even under pathologic conditions the system does not appear to be rate-limiting in the metabolism of bilirubin. 

Since this facilitated transport system allows the equilibrium of bilirubin across the sinusoidal membrane of the hepatocyte, the net uptake of bilirubin will be dependent upon the removal of bilirubin via subsequent metabolic pathways. 

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. 

Increased total, direct, and indirect bilirubin concentrations indicate defects in transport, conjugation, or excretion of bilirubin. 

Cui, Y., et al. Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6J. Biol. Chem. 2001, 276, 9626-9630. 

BBB). It is suggested75 that conformation-stabilizing intramolecularly hydrogen-bonded bilirubin is involved in transport of 90. 

The synthesis, glucuronidation and hepatic transport of new aromatic congeners of bilirubin have also been followed by an RP-HPLC method. The chemical strucutres of bilirubin derivatives are shown in Fig. 2.160. 

J.O. Brower, D.A. Lightner and A.F. McDonagh, Aromatic congeners of bilirubin synthesis, stereochemistry, glucuronidation and hepatic transport. Tetrahedron 57 (2001) 7813-7827. 

Transport of thyroxin and triiodothyronin Maintenance of osmotic pressure transport of fatty acids, bilirubin, bile acids, steroid hormones, pharmaceuticals and inorganic ions. 

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). 

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. 

Excretion of bilirubin into bile Bilirubin diglucuronide is actively transported against a concentration gradient into the bile canaH culi and then into the bile. This energy-dependent, rate-limiting step is susceptible to impairment in liver disease. Unconjugated bilirubin is normally not excreted. 

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