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The excretion and elimination of toxicants and their metabolites

Liver and Biotransformation of Xenobiotics Content: Functional morphology of liver 2. Function of liver 3. Laboratory liver function tests 4. Liver composes of four lobes divided into lobules which are surrounded by blood vessels.

Liver develops as an endodermal hepatic diverticulum of foregut with mesodermal component of septum transversum. The liver is surrounded by fibrous connective tissue capsule — capsule of Glisson. Liver parenchyma consists of hepatic epithelial cells — hepatocytes, arranged in the cellular cords. On the section, these cords remind stripes of cells. In an adult, each cord is formed by one line of cells.

In children approximately until 6 years is each cord formed by two lines of cells. Between these cellular cords are located venous sinuses. These sinusoids are lined by fenestrated discontinuous endothelium which lacks basal lamina. Important components of hepatic sinusoids are Kupffer cells located on the luminal surface of endothelial cells.

Kupffer cells belong to the mononuclear phagocytic system typical macrophages.

  1. In sphyngolipids, sphyngosine is the base.
  2. Hydrophilic molecules and ions are transported via pores. Increased activity of the liver isoenzyme ALP are marker for example of bile ducts obstruction, hepatitides, cirrhosis, liver metastases.
  3. Van der Waals forces, attraction of charges, association between polar and non-polar groups, hydrogen bridges, covalent bonds. Part of urobilinogen is resorbed from the intestine back to the blood and it is transported to the urine.
  4. While these measures are more directly correlated with toxicity, it is still necessary to back-calculate exposure levels associated with these levels for purposes of controlling risks.

The space between basal surface of endothelium and plates of hepatocytes is called the perisinusoidal space space of Disse. The hepatic stellate cells Ito cell are found in perisinusoidal space. These cells store lipid droplets and vitamin A in their cytoplasm. In a pathologic conditions, hepatic stellate cells differentiate into myofibroblasts and synthesize collagen fibers into the space of Disse. This fibrous tissue replaces the hepatocytes, possibly resulting in liver fibrosis which can progress into hepatic cirrhosis.

In the liver, these cells are found: Hepatocytes The hepatocytes are large cells with central nuclei. The hepatocyte cytoplasm contains numerous mitochondria, rough and smooth endoplasmic reticulum, deposits of glycogen, lipid droplets, large number of lysosomes and peroxisomes and multiple Golgi complexes.

The both free sides of hepatocyte have prominent microvilli. Between two surfaces of neighboring hepatocytes, the bile canaliculi are located. Bile canaliculi are the smallest bile canals and their walls are created by surfaces of adjacent hepatocytes. The bile flow direction is opposite to the blood flow from the centre toward the periphery. The terminal parts of bile canaliculi are called canals of Hering.

The canals of Hering already have epithelial lining simple flattened or cuboidal cells called cholangiocytes and they empty into the interlobular bile ductules. Functional organization of the liver parenchyma There is several options how to describe structural organization of liver and thus understand its function.

Specifically, we can use three structural and functional unites — liver lobule, portal lobule and liver acinus. Liver lobule Liver lobule is a classic structural unite describing the organization of liver parenchyme. It is based on the distribution of branches of the portal vein and hepatic artery within the liver.

It is composed by polygonal-shaped parenchyma bordered by thin layer of collagenous connective tissue. In this connective tissue layer, the portal triad is localized. The portal triads composed of the branches of portal vein, hepatic artery and bile duct. One liver lobule contains 3 to 6 portal triads.

Information on Detoxification

The liver lobule itself is composed of anastomosing plates of hepatocytes separated by hepatic sinusoids. Hepatocytes are oriented radially to periphery of lobule. In the centre of lobule is central vein which leads blood into the hepatic veins. Portal lobule The portal lobule lobulus venae interlobularis is a triangular block of liver parenchyma supplied by circumlobular branches of one interlobular vein — at the centre is portal triad and at the peripheral angles are located three central veins.

This lobule represents the portion of hepatic parenchyma that secrete bile that drains into the bile duct of portal triad in the centre of portal lobule. Liver portal acinus The liver acinus is functional unit of liver parenchyma providing the best correlation between blood perfusion, metabolic activity and pathological processes in liver. This ellipse-shaped structure is the smallest functional unit of liver parenchyma. The short axis of acinus is defined by connecting line between adjacent portal triads and the long axis is defined by connecting line between two adjacent central veins.

It remotely resembles two triangles attached together by their bases with central veins in vertices. Between their bases are located the circumlobular vein and artery which supply sinusoids of the liver acinus.

Depending on distance from the circumlobular vein and artery thus depending on distribution of oxygenated blood and nutrientsthree distribution zones are defined.

4. Liver and Biotransformation of Xenobiotics

These elliptical zones surround the short axis of acinus: The oxidative metabolism predominates here e. The reduction processes are predominant in this location — e. This classification is also important for description of pathological conditions — selective damage of hepatocytes. On the basis of described classification, the hepatocytes can be distinguished into periportal and perivenous hepatocytes.

Periportal hepatocytes are the first to receive blood from portal vein and hepatic artery. That is the reason why oxidative metabolism predominate here e. The ammonia detoxification is here represented by synthesis of urea. Perivenous hepatocytes are supplied by poorly oxygenated blood lower pO2 with less nutritions.

Information on Detoxification

The reduction processes are predominant here typically glycolysis, lipid synthesis, biotransformation of xenobiotics on sER. The ammonia detoxification is here represented by glutamine synthesis.

It has important role in 1 maintenance of internal environment i. The liver has also secretory function — it produces bile. The bile is necessary for lipid digestion. It has also another function, it excretes a lot of compounds from the body. The liver has role in immune processes e. Now you can easily deduce that the liver is absolutely necessary for life, therefore severe liver failure leads to death.

Before single functions will be described one important question has to be answered. What are the sources of energy for the liver? This is important because of fact that many functions of the liver are energetically demanding.

Saccharide metabolism It is vital for the body to maintain blood glucose within physiological range i. The liver have so called glucostatic function, it include 1 short-term regulation hours and 2 long-term days, weeks regulation of glycemia.

There are many metabolic pathways that are turned on or off according to glycemia. This changes in activity are caused by hormones produced by endocrine pancreas or adrenal glands. Liver glycogen is buffer of glycemia. There is one key fact: This enzyme allows the liver to release free glucose to the blood stream.

The liver is part of two important interorgan pathways — the Cori cycle and glucose-alanine cycle. Now we describe some metabolic conditions and manner of the liver reaction: This leads to glycogen synthesis in the liver — hepatocytes absorb glucose and produce glycogen. In high glucose excess and full liver glycogen stores is glucose converted to fatty acids and then to TAG. Cytoplasmic membrane of hepatocyte is well permeable for glucose insulin is not necessary.

Apart from mentioned above Glc-6-P may be used for saccharide derivatives synthesis amino saccharides, uronic acids or in the pentose pathway. In the liver also take place 1 conversion of other saccharides to glucose, 2 fructose metabolism, 3 galactose metabolism, 4 amino saccharides synthesis, 5 uronic acids synthesis, and 6 energetic metabolism regulating hormones degradation e. Lipid metabolism The liver is central organ for the excretion and elimination of toxicants and their metabolites metabolism.

Some metabolic pathways of lipids are unique for the liver e. Many pathways take place in other tissues, in the liver these are however quantitatively the most important. Main examples of the lipid metabolism are as follows: In starving the liver oxidize much more fatty acids than it would need for its energy demands. The liver synthesizes ketone bodies ketogenesisketone bodies are released to the circulation for other tissues ketone bodies are utilised only in extrahepatic tissues.

The liver in the same time use also second compound of TAG — glycerol. Glycerol is substrate for glucose production — gluconeogenesis. The liver is the main location of glucose conversion to pyruvate.

Glucose used for this conversion comes from excessive saccharide income. Part of fatty acids is used for phospholipid synthesis. All of these take place in the liver. Part become a part of lipoproteins and thus it is transported to the extrahepatic tissues, part is excreted to the bile cholesterol also as the bile acids.

In smooth endoplasmic reticulum of hepatocytes cholesterol excess is converted to bile acids by hydroxylases that use O2, NADPH, cytochrome P450. Protein and amino acids metabolism The most important processes in protein and amino acids metabolism that take place in the liver are as follows: Amino acids come to the liver as products of 1 digestion of ingested proteins or 2 degradation of body proteins. Amino acids undergo specific reactions in hepatocytes — e.