Bilirubin hepatic Uptake

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

B29. Brown, W. R., Grodsky, G. M., and Carbone, J. V., Intracellular distribution of tritiated bilirubin during hepatic uptake and excretion. Amer, J. Physiol. 267, 1237-1241 (1964). 

L8. Levi, A. J., Gatmaitan, Z., and Arias, I. M., Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein, and other anions. J. Clin. Invest. 48, 2156-2167 (1969). 

Figure 22-3. Transport and hepatic metabolism of bilirubin. Bilirubin that is produced in phagocytes is transported to liver as an albumin-bilirubin complex. Uptake into the hepatocytes takes place in liver sinusoids. Within the hepatocyte, bilirubin is transported to the endoplasmic reticulum (microsomes) bound to glutathione S-transferase (GST). Bilirubin is made water soluble by addition of one or two glucuronic acid moieties obtained from UPD-glucuronic acid, catalyzed by bilirubin-UDP-glucuronyltransferase. The product, conjugated bilirubin, is transported across the bile canalicular membrane for secretion into the biliary system, with subsequent movement into the intestines.

Rifampicin impairs hepatic uptake and excretion of bilirubin plasma xmconjugated and conjugated bilirubin may be elevated during the first 2-3 weeks of dosing. 

The entry step seems to be carrier-mediated, is saturable, is reversible, and is competitively inhibited by sul-fobromophthalein, indocyanine green, cholecystographic agents, and several drugs. Bile salts do not compete with bilirubin for hepatic uptake. 

Reduced BSP removal in neonates is probably due to an insufficient rate of excretion into the bile because hepatic uptake and conjugation are adequate (V7, V8). However, changes in BSP handling with age in neonates has been attributed to circulatory changes (01). No correlation has been found between plasma bilirubin and BSP retention in the neonatal period (M28, Yl). 

Novobiocin has been associated with hyperbilirubinemia in the newborn (S46), and it has been shown to depress the excretion of BSP (B21a) and indocyanine green (H4, H5) as well as the maximal excretion rate for bilirubin (A3). Novobiocin also inhibits the excretion of bilirubin by liver slices (H5). Novobiocin was found to inhibit the glucuronyl transferase (H4), but this could be secondary to an accumulation of the conjugated bilirubin after inhibition of the excretory mechanism. Novobiocin, in contrast to other agents, also inhibits hepatic uptake of dyes and this may be its main effect (B21a). 

Plasma bile acids (total bile acids, TBAs) have been recommended as an alternative measurement to plasma bilirubin because TBAs can indicate biliary functionality in terms of the response to food intake. TBA values are dependent upon a number of factors, including stomach emptying gall bladder contraction, where it exists intestinal motility intestinal absorption hepatic uptake and hepatic excretion. The enterohepatic circulation amplifies deficiencies in the hepatic transport system this results in reduced secretion of bile acids into the bile. Studies with dogs have shown that timed postprandial measurements have greater diagnostic value than fasting or random samples (Center et al. 1991 Jensen and Poulsen 1992), but the collection of timed postprandial samples is more difficult. 

Glucuronyl transferase (UDP-glncuronate biliru-bin-glucuronyltransferase) (EC 2.4.1.76). Enzyme completely absent. Severe jaundice and brain encephalopathy. Often death in infancy. Conjugation is obligatory for excretion of bilirubin. In a milder form of the disease some enzyme is present, and treatment is possible by administration of phenobar-bital, which stimulates hepatic uptake, conjugation and biliary secretion (as glucuronide) of bilirubin. 

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

Indocyanine green was introduced by J. Caesar et al. in 1961 as a liver function test. Anionic tricarbocyanine dye is referred to as an ideal test substance (1.) it is tolerated very well there have been no reports of any incidents so far, and even paravenous injection is tolerated (2.) it is excreted unchanged by hepatocytes in the bile as there is no bio transformation - this is why ICG clearance is valid as a measure of hepatocellular uptake and transport processes (3.) there is no interference with drugs (except rifamycin), haemolysis, bilirubin (up to approx. 4 mg/dl) or hyperlipidaemia (4.) the substance is not subject to the enterohepatic circulation (J.) the rapid elimination, which depends on hepatic perfusion ( flow-limited ), allows the calculation of the hepatic flow volume as a whole based on ICG clearance (6.) the method is simple to perform. 

Hepatic extraction efficiency decreases with increasing serum bilirubin levels. With impaired hepatocyte function, high plasma concentrations (>8 mg/100 ml) may inhibit uptake of Tc-IDA complexes. As hepatobiliary excretion decreases, renal accumulation of certain " Tc-IDA complexes is observed (Fink-Bennett 1995). 

The bilirubin transported in the plasma is eliminated from it by uptake in the liver cell. Again, the mechanism of transfer of bilirubin from plasma to hepatic cell is not known. 

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