1. LIVER BIOCHEMISTRY

2. Liver Largest internal organ Weighs about 1400-1800 gram Located on right side under ribcage Ability to regenerate Has over 500 vital functions Involved in many digestive, vascular and metabolic activities

4. portal vein hepatic artery bile duct sinusoids bile canaliculi central vein LIVER STRUCTURE

5. The following processes take place in the liver: 1. The creation of bile pigments synthesis of cholesterol, synthesis and secretion of bile. 2. The detoxication of toxic products, coming from gastrointestinal tract. 3. The synthesis of proteins (proteins of plasma of blood among them), their deposition, transamination and desamination of aminoacids, the formation of urea, the synthesis of creatinine. 4. The synthesis of glycogene from monosaccharides. 5. The oxidation of fatty acids, the formation of acetone (ketone bodies). 6. The deposition and exchange of vitamins (А, В, D), the deposition of iron, copper, zinc ions. 7. The regulation of the balance between coagulant and anticoagulant blood system, the formation of heparine. 8. The destruction of some microorganisms, bacterial and other toxins. 9. The deposition of plasma of blood, the regulation of a total amount of blood. 10. Hemopoiesis in the fetus.

6. Functions of the Liver TypeFunction Metabolic Absorptive PeriodConverts glucose to glycogen and triglycerides; stores glycogen. Converts amino acids to fatty acids or stores amino acids. Makes lipoprotein from triglycerides and cholesterol. Postabsorptive Period Produces glucose from glycogen (glycogenolysis) and fatty acids and amino acids (glyconogenesis). Converts fats to ketones (accelerated if fasting). Produces urea from protein catabolism. Immunologic Metabolic Transformation Macrophages filter blood. Detoxifies or conjugates waste products, hormones, drugs. Clotting FunctionsProduces several essential clotting factors. Plasma ProteinsSynthesizes albumin and other plasma proteins. Exocrine Functions Synthesizes bile salts. Endocrine Functions Involved in activation of vitamin D. Produces angiotensinogen. Secretes insulin-like growth factors (somatomedin).

10. Liver’s functions 1.Liver is a main organ which is responsible for dividing of nutritional substances in our organism (for example, glucose, triacylglicerides and ketone bodies). 2. Hepatocytes synthesizes as lot of blood plasma proteins and lipoproteins, low-weight bioactive substances (creatin, 25- oxicalciferol, hem), cholesterol. 3. Synthesis of urea (final product of nitrogen metabolism) also takes place in the liver.

11. Liver’s functions 4. Liver synthesizes bile acids and excrete a bile into intestinal tract. This process plays a very important role in lipids digestion and excretion of cholesterin and some products of metabolism into intestine. 5. Liver play a big desintoxification role, inactivates endogenic and exogenic substances (drugs, some hormones, different toxins). 6. Liver is a depo for iron, some another metals, vitamines A, D, E, B12, folic acid.

14. Role of the liver in carbohydrate metabolism  From intestine glucose pass into the liver, where most part of it undergone the phosphorillation. Glucose-6-phosphate formed in result of this reaction, which catalyzed by two enzymes – hexokinase and glucokinase.  Glucose-6-phosphate is a key product of carbohydrates metabolism. In the liver this substance can metabolized into different ways depend of liver’s and whole organism’s necessity.

15. Glucose The fate of glucose molecule in the cell Glucose-6- phosphate Pyruvate Glycogen Ribose, NADPH Pentose phosphate pathway supplies the NADPH for lipid synthesis and pentoses for nucleic acid synthesis Glycogenesis (synthesis of glycogen) is activated in well fed, resting state Glycolysis is activated if energy is required Glycogenolysis (degradation of glycogen) Gluconeoge nesis is activated if glucose is required TCA cycle

16.  Synthesis of glycogen. Content in the liver – 70- 100g  Glucose-6-phosphatase catalize dephosphorillation of glucose-6-phosphate and formation of free glucose  Excess of glucose-6-phosphate, which not used for synthesis of glycogen will follow to form free glucose  Glucose-6-phosphate decomposed to H 2 O and CO 2, and free energy for hepatocytes formed. Role of the liver in carbohydrate metabolism

17.  Part of glucose-6-phosphate oxidized in pentosophosphate cycle.  Hepatocytes content full set of gluconeogenesis necessary enzymes. So, in liver glucose can be formed from lactate, pyruvate, amino acids, glycerol.  Gluconegenesis from lactate takes place during intensive muscular work. Lactate formed from glucose in muscles, transported to the liver, new glucose formed and transported to the muscles Role of the liver in carbohydrate metabolism

18. METABOLISM OF CARBS IN LIVER Summary: METABOLISM OF CARBS IN LIVER  glycolisis  metabolism of fructose and galactose  gluconeogenesis  release of glucose into blood (maintain the stable glucose concentration in blood)  conversion of pyruvate into acetyl CoA  tricarboxylic acid cycle  pentose phosphate pathway  glycogenolysis, glycogenogenesis

19. Role of the liver in lipid metabolism In the liver all processes of lipid metabolism take place. Most important of them are following: Lipogenesis (synthesis of fatty acids and lipids). Substrate for this process – acetyl-CoA, formed from glucose and amino acids, which are not used for another purposes Liver more active than another tissues synthesizes saturated and monounsaturated fatty acids. Fatty acids then used for synthesis of lipids, phospholipids, cholesterol ethers.

20. Role of the liver in lipid metabolism Liver play a central role in synthesis of cholesterin, because near 80 % of its amount is synthesized there. Biosynthesis of cholesterin regulated by negative feedback. When the level of cholesterin in the meal increases, synthesis in liver decreases, and back to front. Besides synthesis regulated by insulin and glucagon. Liver is a place of ketone bodies synthesis. These substances formed from fatty acids after their oxidation, and from liver transported to another tissues, first of all to the heart, muscles, kidneys and brain

24. Role of the liver in protein metabolism Liver has full set of enzymes, which are necessary for amino acids metabolism. Amino acids from food used in the liver for following pathways: protein synthesis, including blood plasma proteins protein decomposition; urea synthesis Transformation to the carbohydrates and lipids. interaction between amino acids. conversion of proteins into low molecular weight nitrogen containing substances transformation to the different substances with amino group. release to the blood and transport to another organs and tissues.

25.  Liver synthesizes 100 % of albumins, 90 % of α1-globulines, 75 % of α2-globulines,50 % of β-globulins, blood clotting factors, fibrinogen, protein part of blood lipoproteins, such enzyme as cholinesterase.  Liver can synthesize non-essential amino acids.  Liver synthesizes purine and pyrimidine nucleotides, hem, creatine, nicotinic acid, choline, carnitine, polyamines.

26. Role of the liver in detoxification processes A xenobiotics is a compound that is foreign to the body. The principal classes of xenobiotics of medical relevance are drugs, chemical cancerogens, and various compounds that have found their way into our environment by one route or another (insecticides, herbicides, pesticides, food additions, cosmetics, domestic chemical substances).

27. Role of the liver in detoxification processes Some internal substances also have toxic properties (for example, bilirubin, free ammonia, bioactive amines, products of amino acids decay in the intestine). Moreover, all hormones and mediatores must be inactivated. Reactions of detoxification take place in the liver. Big molecules like bilirubin excreted with the bile to intestine and leaded out with feces. Small molecules go to the blood and excreted via kidney with urine.

28. REACTIONENZYMELOCALIZATION PHASE I Hydrolysis Reduction Oxidation Esterase Peptidase Epoxide hydrolase Azo- and nitro-reduction Carbonyl reduction Disulfide reduction Sulfoxide reduction Alcohol dehydrogenase Aldehyde dehydrogenase Aldehyde oxidase Xanthine oxidase Monoamine oxidase Diamine oxidase Flavin-monooxygenases Cytochrome P450 Microsomes, cytosol, lysosomes, blood lysosomes Microsomes, cytosol Microflora, microsomes, cytosol Cytosol, blood, microsomes Cytosol Mitochondria, cytosol Cytosol Mitochondria Cytosol Microsomes PHASE II Glucuronide conjugation Sulfate conjugation Glutathione conjugation Amino acid conjugation Acetylation Methylation Microsomes Cytosol, microsomes Cytosol Mitochondria, cytosol Mitochondria, microsomes Cytosol, microsomes, blood General ways of xenobiotics biotransformation and their localization in cell

29. The metabolism of xenobiotics has 2 phases: In phase 1, the major reaction involved is hydroxylation, catalyzed by members of a class of enzymes referred to as monooxygenases or cytochrome P-450 species. These enzymes can also catalyze deamination, dehalogenation, desulfuration, epoxidation, peroxidation and reduction reaction. Hydrolysis reactions and non-P-450-catalyzed reactions also occur in phase 2.

32. [ 1] In the resting state, the heme iron is trivalent. Initially, the substrate binds near the heme group. [2] Transfer of an electron from FADH2 reduces the iron to the divalent form that is able to bind an O2 molecule. [3] Transfer of a second electron and a change in the valence of the iron reduce the bound O2 to the peroxide. [4] A hydroxyl ion is now cleaved from this intermediate. Uptake of a proton gives rise to H2O and the reactive form of oxygen mentioned above. In this ferryl radical, the iron is formally tetravalent. [5] The activated oxygen atom inserts itself into a C–H bond in the substrate, thereby forming an OH group. [6] Dissociation of the product returns the enzyme to its initial state.

34. In phase 2, the hydroxylated or other compounds produced in phase 1 are converted by specific enzymes to various polar metabolites by conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation.

35. Transformation of hormones inactivation of steroid hormones – hydrogenation, conjugation inactivation of insulin and glucagon (see next page) inactivation of catecholamines and iodothyronines – conjugation dehydrogenation of cholesterol to 7- dehydrocholesterol and 25-hydroxylation of calciols play an essential role in calcium homeostasis