Liver canaliculi

BCRP (also known as ABCG2) is a half ABC transporter. It is sometimes known as mitoxantrone resistance protein (MXR) because of its elevated expression in many cancer cell lines selected with mitoxantrone [54]. BCRP was first identified in breast cancer, but it is also found in several normal tissues, including placenta, liver canaliculi, small intestine, colon, the bronchial epithelial layer in the lung, and endothelial cells [55]. Its level is also elevated in other cancer types. For instance, an analysis of 150 untreated tumors with immuno-histochemical technique demonstrated a high incidence of BCRP overexpression particularly in tumors of gastrointestinal origin [56]. Elevated BCRP level is consistently associated with the phenotype that includes strong resistance to mitoxantrone, moderate resistance to anthracyclines, and sensitivity to... 

In the case of intestine, one can observe an orderly array of spheres arranged on the outer leaflet, both of which, along with the inner leaflet, are sites of reaction product for alkaline phosphatase. The photograph of the mouse liver canaliculi does not reveal these details at a magnification of 23,000. 

Hepatocytes make up 60-70% of the total number of liver cells. They have a well-organized intracellular structure with huge numbers of cell organelles to maintain the high metabolic profile. At the apical side or canalicular membrane the cell is specialized for the secretion of bile components. There are several ATP-dependent transport carriers located on this side of the membrane, which transport bile salts, lipids and xenobiotics into the canaliculus. On the sinusoidal side, the cells specialize in uptake and secretion of a wide variety of components. To increase the surface of the membrane for this exchange with the bloodstream, the sinusoidal domain of the membrane is equipped with irregular microvilli. The microvilli are embedded into the fluid and matrix components of the space of Disse and are in close contact with the sinusoidal blood because of the discontinuous and fenestrated SECs. To facilitate its metabolic functions numerous membrane transport mechanisms and receptors are situated in the membrane. 

In the liver drugs are predominantly taken up by the hepatocytes, e.g. by carrier-mediated uptake, metabolized in the hepatocyte and excreted either via the bile canaliculus into the bile or back into the bloodstream, e.g. by carrier-mediated excretion. 

Many drugs that are taken up and metabolized by hepatocytes are excreted via the bile canahcuh into the bile. One of the remaining topics in liver slice research is the question of whether liver shces are capable of bile excretion via the bile canaliculus. Thompson et aZ.[93] showed that shces are capable of excreting bile acids, however, there is a need for more experiments to determine whether this excretion takes place across the bile canalicular membrane. 

Serum ALP and total bilirubin (unconjugated and conjugated fractions) are traditionally used to monitor cholestatic injury. The ALP families of enzymes are zinc metalloproteases that are present in nearly all tissues. In the liver, ALP is immu-nolocalized to the microvili of the bile canaliculus [124]. Increased synthesis of ALP and its release into the circulation occurs within hours of cholestatic injury [129]. Serum assays of 5 -nucleotidase (5 -NT) or y-glutamyltransferase activity (GGT) are used to confirm the liver as the specific origin for the elevation of ALP. Increases in serum bilirubin or bile acids are usually the result of bile retention subsequent to impaired bile flow, increased production associated with accelerated erythrocyte destruction, or altered bilirubin metabolism [129]. 

Multi-drug resistance protein-2 (MRP-2) A protein in the bile canaliculus of liver cells involved in the hepatobiliary transport of organic chemicals. 

The bile canaliculus is formed as a bile capillary by means of a groove-like canal in the intercellular space, bounded by 2 adjacent liver cells. The bile canaliculi have no walls of their own, but are surrounded by a special zone of the cell membrane (so-calledpericanalicular ectoplasm). Their diameter amounts to 0.5-1.0 pm. They are interconnected and form an extensive polygonal network. The surface area of the bile capillaries is increased by microvilli, which show great functionally determined variability. The canalicular membrane constitutes 10% of the total plasma membrane in the hepatocytes. Similar to the pericanalicular ectoplasm, the hepatocytes contain contractile microfilaments and other components of the cytoskel-eton. These canaliculi are supplied with carrier proteins and enzymes to control bile secretion. (2,34)... 

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. 

The exclusive presence of lanthanum in the bile and in the lysosomes of the liver cell is consistent with excretion of lanthanum by the liver via the transferrin receptor-endosomal-lysosomal-bile canaliculus pathway [41]. Clinical studies of up to 4 years have not... 

The patient receives an intravenous injection of S tnC (185 MBq) of Tc-99m disofenin. which is taken upbtlh-hepatocytes in the liver by active anionic transport. Hu the radiopharmaceutical is excreted in bile, via the biliin canaliculus, into the bile ducts, with accumulation in ll. gallbladder and finally excretion via the common bileilij,i into the small bowel. The normal patient exhibits early xa mulation of the radiopharmaceutical in the liver and the pi bladder and small bowel can be visualized within I u. hours after injection. An example is seen in Figure 1. 3... 

Figure 47-4 Portions of two human liver cells showing the relationship of the organelles and a typical bile canaliculus (BC). Arrowheads indicate light junctions, N, Nucleus M, mitochondria Mb, microbody G, Golgi SER, smooth endoplasmic reticulum L, lysosome g, glycogen. (From Zakim 0, Boyer TD. Hepatology A tejctbook of liver disease, 3rd ed. Philadelphia WB Saunders, 1996 20.)...

A key feature of the liver is the antidromic blood and bile flow system (Fig. lc). Blood enters the lobules in the periphery, passes the sinusoids, and is drained off into the central vein. Bile is secreted by the hepatocytes into the apical bile canaliculi, which form a network organized parallel as well as perpendicular to the sinusoidal vessels. Bile flows to the bile ducts in the periportal field and is finally drained off into the gall bladder and the small intestine. The bile canalicular network is not composed of conventional vessels with endothelial cells. It is formed by the apical membrane of hepatocytes and thereby is a consequence of the polar structure of these cells which have an apical pole (facing the bile canaliculus) and a basolateral side (facing the sinusoid). The direct contact to bile leads to a high vulnerability of hepatocytes. Destruction of the apical hepatocyte membrane may lead to bile acids entering the cell, hepatocyte killing, and inflammation. 

Bile produced by hepatocytes is secreted into the bile canaliculi between adjacent hepatic cells. The wall of the canaliculus is formed by the plasma membrane of the hepatocytes, which are held together by tight junctions. Canaliculi arise near central veins and extend to the periphery of the lobules. The direction of bile flow in the canaliculi is centrifugal, whereas that of the blood flow is centripetal. Canaliculi coalesce to form ducts, which are lined by epithelium, and the ducts coalesce to form the right and left hepatic ducts. Outside the liver these ducts form the common hepatic duct. 

Bile acids, which have been taken up by the liver, are transported across the hepatocyte and secreted into the bile canaliculus. Newly synthesized bile acids, in a small amount just sufftcient to balance the fraction lost by fecal excretion, join recycled bile acids for biliary secretion. Intracellular bile acid transport may be mediated by carrier proteins (B24, S42). The detailed mechanism of biliary secretion of bile acids and other organic anions into the bile canaliculus is not yet clear (B24). Possible mechanisms include vectorial vesicular transport, fticilitated diflusion, or an energy-requiring carrier-mediated transport process (B24). 

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. 

If it is of interest that biliary storage of BSP in patients with the Dubin-Johnson syndrome fell within the normal range (52,53), allowing the possibility that the mechanism for the extraction of the dye from plasma by the liver is unimpaired. Thus one may speculate that the site of competition between bile salts and anionic dyes is at the hepatic uptake (or storage) stage and that subsequent secretion from the cell into the canaliculus of the two substances may proceed by separate mechanisms. 

Fig. 7. Electronmicrograph of alkaline phosphatase reaction in a bile canaliculus of adult mouse liver. The reaction product is present on the microvilli and does not extend in the intercellular spaces beyond the terminal bar. X 23,000. (Hugon, 1972.)...

Fig. 18. Liver of rat pulse-labeled by incubation for 5 minutes with choline- H and chased for 25 minutes. The radioautographic reaction, which represents labeled lecithin, is seen over the sinusoidal cell boundary, over elements of smooth and rough endoplasmic reticulum, mitochondria, and bile canaliculus, x 18,000. (From O. Stein and Stein, 1969, reproduced by permission of the Editor of. Cell Biol.)... 

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