Bile, bilirubin secretion into

In the hver, bilirubin is made water-soluble by conjugation with two molecules of glucuronic acid and is secreted into the bile. The action of bacterial enzymes in the gut produces urobihnogen and urobihn, which are excreted in the feces and urine. 

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.

The transfer of conjugated bilirubin in the hepatocyte across the bile canaliculus deposits the conjugated bilirubin along with other hepatic secretions into the biliary system for transport to the small intestine. This transport process is catalyzed by one or more members... 

Although the liver is commonly identified with its primary role of drug metabolism, one of the main functions of the liver is the formation of bile. BUe forms in the canaliculus between adjacent hepatocytes following active secretion bUe acids and other components (phospholipids, bilirubin, cholesterol) across the canalicular membrane. These components are either synthesized by the liver or transported into the hepatocyte across the sinusoidal membrane. Bile acid secretion stimulates osmotic water flow across the canalicular membrane. The resulting bile drains into branches of intrahepatic bile ductules that converge to the common hepatic bUe duct. In humans, 500 to 600 ml of bile is produced daily. 

Bilirubin diglucuronide is secreted into the bile capillaries and constitutes some 15-20% of the dry weight of the bile. Only negligible amounts... 

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. 

Figure 32-15. Diagrammatic representation of the three major processes (uptake, conjugation, and secretion) involved in the transfer of bilirubin from blood to bile. Certain proteins of hepatocytes, such as ligandin (a family of glutathione S-transferase) and Y protein, bind intracellular bilirubin and may prevent its efflux into the blood stream. The process affected in a number of conditions causing jaundice is also shown.

This benign autosomal recessive disorder consists of conjugated hyperbilirubinemia in childhood or during adult life. The hyperbilirubinemia is caused by mutations in the gene encoding MRP-2 (see above), the protein involved in the secretion of conjugated bilirubin into bile. The centrilobular hepatocytes contain an abnormal black pigment that may be derived from epinephrine. 

Impaired liver function or blocked bile secretion causes bilirubin to leak from the liver into the blood, resulting in a yellowing of the skin and eyeballs, a con-... 

Bile is a mixture of electrolytes, bile acids, cholesterol, phospholipids and bilirubin. Adults produce between 400 and 800 ml of bile daily. Hepatocytes secrete bile into canaliculi, then into bile ducts, where it is modified by addition of a bicarbonate-rich secretion from ductal epithelial cells. Further modification occurs in the gall bladder, where it is concentrated up to fivefold, through absorption of water and electrolytes. Gallstones, most of which are composed... 

This volume of secretion is supplemented in the ductules by ca. 150 ml ductular bile, resulting in a daily production of ca. 600 ml. Bile formation is lower at night than during the day. The most important constituents of the so-called liver bile are the bile acids, phospholipids, proteins, cholesterol and bilirubin. The term bile lipids includes cholesterol, bile salts and phospholipids. The manner in which cholesterol is excreted into the gall bladder is not yet known, nor have any cholesterol-specific transport systems been detected. Cholesterol is primarily broken down into bile acids, (see above) (s. tab. 3.5)... 

Biochemically, a change in structure relating to the mucopolysaccharides (neuraminic add ) and monohydroxy bile acids probably accounts for the formation of biliary thrombi. Some of the under-hydroxylated bile salts appear in crystalline form the bile becomes increasingly viscous and its flow is impeded. This defect in the excretion of bile salts culminates in dysfunctions in the secretion of bilirubin, which is why bilirubin is regurgitated into the blood. The bile which accmnulates in the bile ducts ultimately becomes mucous and white because of the reabsorption of bile pigments by the epitheha of the small bile ducts. 

I he average daily intake of total dietary cholesterol is 400-500 mg. Cholesterol also enters the gastrointestinal tract via the bile. Between fiOO and 1200 mg of free cholesterol is secreted in the bile per day. By weight, bile consists of 92% water, 6% bile salts, 0,3% cholesterol, and small amounts of bilirubin, fatty acids, phosphatidylcholine, and sails. The cholesteryl esters of the diet are hydmlyzed to free cholesterol and a fatty add by pancreatic cholesterol esterase. After entry into the enterocyte, the free cholesterol is nmverted back to cholesteryl esters by acyl CoA cholesterol acyl transferase. Some evidence suggests that the absorption of dietary cholesterol (from the bile salt micelles) is mediated by a membrane-bound transport protein of the brush border (1 humhofer and Hauser, 1990),... 

Secretion across the canalicular membrane into bile appears to be the rate-limiting step in hepatic bilirubin metabolism. It is probably carrier-mediated, requires energy, is saturable, and is unaffected by bile salts. Bilirubin can be made water-soluble by conversion to its configurational isomers. These photobilirubins are formed when bilirubin is exposed to blue light of the 400- to 500-nm wavelength (Figure 29-14). Photobilirubins cannot form the intramolecular hydrogen bonds characteristic of the... 

The primary blocks to bilirubin metabolism are low activity of bilirubin glucuronyltransferase and low concentration of ligandin in the liver at birth. Secretion of conjugated bilirubin into the bile is also reduced. 

Bile fluid performs two important functions (1) the emulsification, solubilization, and transport of lipids and fat-soluble vitamins by the detergent effects of bile acids, and (2) the elimination of many waste products, including bilirubin and cholesterol secreted via the bile into the gastrointestinal tract. Bile acids and bile salts are the principal components of the bile fluid, acting as detergents in the digestion of fat in the intestinal tract. 

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. 

A fraction of the intestinaly excreted polymer may be transported into the intestinal lumen with the bile. Bile is produced by the liver parenchymal cells (hepatocytes) by active secretion in the sense that the hepatocytes transform and transport blood components, bile acids and bilirubin into the bile canaliculi. There are some indications that macromolecules and even particles, e.g. colloidal mercuric sulfite, colloidal Ag, can be eliminated from blood in the bile although this elimination is slow. De... 

This deficiency happens to be related to one of the polymorphic phenotypes of esterase-3, and the resulting lack of liver microsomal (3-glucuronidase is not the cause of hyperbilirubinuria. The disturbed metabolism of bilirubin was shown to be due to blocking of secretion of conjugated bilirubin into bile (Hosokawa et al., 1992). 

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