Hepatocytes Schematic Arrangement In Liver

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As it is one of the portals of entry to the tissues of the body, the liver is exposed to many potentially toxic substances via the gastrointestinal tract from the diet, food additives and contaminants, and drugs and is frequently a target in experimental animals. In man, liver damage is less common and only around 9% of adverse drug reactions affect the liver. By virtue of its position, structure, function and biochemistry the liver is especially vulnerable to damage from toxic compounds. Substances taken into the body from the gastrointestinal tract are absorbed into the hepatic-portal blood system and pass via the portal vein to the liver. Thus, after the gastrointestinal mucosa and blood, the liver is the next tissue to be exposed to a compound, and as it is prior to dilution in the systemic circulation, this exposure will often be at a higher concentration than that of other tissues. The liver, the largest gland in the body, represents around 2-3% of the body weight in man and other mammals such as the rat. It is served by two blood supplies, the portal vein which accounts for 75% of the hepatic blood supply, and the hepatic artery. The portal vein drains the gastrointestinal tract, spleen and pancreas and therefore supplies nutrients, and the hepatic artery supplies oxygenated blood (figure 6.2). The liver receives around 25% of the cardiac output, which flows through the organ at around 1-1.3 ml/min/g and drains via the hepatic vein into the inferior vena cava. In between the blood entering the liver via hepatic artery and portal vein and leaving via the hepatic vein, the blood flows through sinusoids (figure 6.3). Sinusoids are specialized capillaries with discontinuous basement membranes which are lined with Kupffer cells and endothelial cells. There are large fenestrations in the sinusoids which allow large molecules to pass through into the interstitial space and into close contact with the hepatocytes (figure 6.4). The liver is mainly composed of hepatocytes arranged as plates approximately two-cells thick, each plate bounded by a sinusoid (figure 6.4). The membranes of adjacent

Liver Vasculature
FIGURE 6.2 The vasculature supplying and draining the liver and its relationship to the systemic circulation. From Timbrell, J.A., Biotransformation of xenobiotics. From General and Applied Toxicology, 2nd edition, edited by Ballantyne, Marrs andSyversen, Stockton Press, U.S.A.

FIGURE 6.3 Schematic representation of the arrangement and relationship of vessels and sinusoids in the liver. The central vein drains into the hepatic vein. From Timbrell, J.A., The liver as a target organ for toxicity, in Target Organ Toxicity, edited G.M.Cohen (Boca Raton, Fl.: CRC Press), 1989, with permission.

FIGURE 6.3 Schematic representation of the arrangement and relationship of vessels and sinusoids in the liver. The central vein drains into the hepatic vein. From Timbrell, J.A., The liver as a target organ for toxicity, in Target Organ Toxicity, edited G.M.Cohen (Boca Raton, Fl.: CRC Press), 1989, with permission.

hepatocytes form the bile canaliculi into which bile is secreted. The bile canaliculi form a network which feed bile into ductules which become bile ducts (figure 6.3).

The structural and functional unit of the liver is the lobule, which is usually described in terms of the hepatic acinus (figure 6.5), based on the microcirculation in the lobule. When the lobule is considered in structural terms it may be described as either a classical or a portal lobule (see glossary). The acinus comprises a unit bounded by two portal tracts and terminal hepatic or central venules, where a portal tract is composed of a portal venule, bile ductule and hepatic arteriole (figure 6.5). Blood flows from the portal tract towards

Pathocyte Sch
FIGURE 6.4 Diagrammatic representation of the arrangement of hepatocytes within the liver and the relationship to the sinusoids. From Timbrell, J.A., The liver as a target organ for toxicity, in Target Organ Toxicity, edited G.M. Cohen (Boca Raton, Fl.: CRC Press), 1989, with permission.
Liver Hepatocyte Arrangement

FIGURE 6.5 Schematic representation of a hepatic acinus. PT represents the portal tract, consisting of branches of the portal vein and hepatic artery and a bile duct. CV represents a branch of the central vein. The areas 1, 2 and 3

FIGURE 6.5 Schematic representation of a hepatic acinus. PT represents the portal tract, consisting of branches of the portal vein and hepatic artery and a bile duct. CV represents a branch of the central vein. The areas 1, 2 and 3

represent the various zones draining the terminal afferent vessel. Adapted from Rappaport, A.M. (1969) In Diseases of the Liver, edited by L.Schiff (Philadelphia: J.B.Lippincott).

the central venules, whereas bile flows in the opposite direction. There are three circulatory zones in the acinus, with zone 1 receiving blood from the afferent venules and arterioles first, followed by zone 2 and finally zone 3. Thus, there will be metabolic differences between the zones because of the blood flow. Zone 1 will receive blood which is still rich in oxygen and nutrients, such as fats and other constituents. The hepatocytes in zone 3, however, will receive blood which has lost much of the nutrients and oxygen. Zone 1 approximates to the periportal region of the classical lobule and zone 3 to the centrilobular region. Zone 3, particularly where several acini meet, is particularly sensitive to damage from toxic compounds. The acinus is also a secretory unit, the bile it produces flowing into the terminal bile ductules in the portal tract.

The close proximity of the blood in the sinusoids with the hepatocytes allows efficient exchange of compounds, both endogenous and exogenous and consequently foreign

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compounds are taken up very readily into hepatocytes. For example, the drug propranolol is extensively extracted in the 'first pass' through the liver.

The liver is a target organ for toxic substances for four main reasons:

a The large and diverse metabolic capabilities of the liver enable it to metabolize many foreign compounds, but as metabolism does not always result in detoxication this may make it a target (see Chapter 7, carbon tetrachloride and paracetamol). b The liver also has an extensive role in intermediary metabolism and synthesis and consequently interference with endogenous metabolic pathways may lead to toxic effects, as discussed in Chapter 7 (see galactosamine and ethionine). c The secretion of bile by the liver may also be a factor. This may be due to the biliary excretion of foreign compounds leading to high concentrations, especially if saturated as occurs with the hepatotoxic drug furosemide. Alternatively, enterohepatic circulation can give rise to prolonged high concentrations in the liver. Interference with bile production and flow as a result of precipitation of a compound in the canalicular lumen or interference with bile flow may lead to damage to the biliary system and surrounding hepatocytes. d The blood supply ensures that the liver is exposed to relatively high concentrations of toxic substances absorbed from the gastrointestinal tract.

The hepatocytes, or parenchymal cells, represent about 80% of the liver by volume, and are the major source of metabolic activity. However, this metabolic activity varies depending on the location of the hepatocyte. Thus zone 1 hepatocytes are more aerobic and therefore are particularly equipped for pathways such as the ^-oxidation of fats, and they also have more glutathione and glutathione peroxidase. These hepatocytes also contain alcohol dehydrogenase and are able to metabolize allyl alcohol to the toxic metabolite acrolein which causes necrosis in zone 1. Conversely, zone 3 hepatocytes have a higher level of cytochromes P-450 and NADPH cytochrome P-450 reductase, and lipid synthesis is higher in this area. This may explain why zone 3 is the most often damaged and lipid accumulation is a common response (see carbon tetrachloride for instance; Chapter 7). The Kupffer cells are known to contain significant peroxidase activity and also acetyltransferase. The differential distribution of isoenzymes may also be a factor in the localisation of damage. There are various types of toxic response which the liver sustains which reflect its structure and function. Viewed simply, liver injury is usually due either to the metabolic capabilities of the hepatocyte or involves the secretion of bile.

The various types of liver damage which may be caused by toxic compounds are discussed in the following sections.

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