GIT Biochemistry PDF

Course Name: GIT Prof. Dr. Riyadh Saif-Ali Gastrointestinal Tract Biochemistry  Gastrointestinal Tract System Topics Contact Hours Composition of GIT Secretions & its Regulation (including GIT Hormones) 5 Activation of Digestive Enzymes Mec...

Course Name: GIT Prof. Dr. Riyadh Saif-Ali Gastrointestinal Tract Biochemistry  Gastrointestinal Tract System Topics Contact Hours Composition of GIT Secretions & its Regulation (including GIT Hormones) 5 Activation of Digestive Enzymes Mechanism of Nutrients Absorption 1 Disorders of GIT Secretions 2 Maldigestion & Malabsorption 2 Xenobiotic metabolism Phase 1 4 Phase 2  Trigger 1: A forty-year-old man who had been a heavy drinker for many years, went to see his general practitioner. He had made two previous visits over the past year due to his experiencing recurrent episodes of abdominal pain. Although the pain had been intermittent at first, it was now continuous. The patient also said that he had lost a considerable amount of weight since his last visit. Upon enquiry the pain was described to originate in the epigastrium, and to radiate through to the back. In appearance the patient was very thin and the doctor noticed that he was mildly jaundiced. The doctor arranged for the patient to be admitted to hospital for a few days for tests so that his condition could be diagnosed.  Trigger 2: serum pancreatic amylase (low) Bilirubin and alkaline phosphatase (elevated) glucose tolerance test: high and prolonged rise in serum glucose, Urine analysis confirmed the presence of glycosuria. Stool: pale-coloured and bulky, indicating a high fat content (steatorrhea). Secretin test was also requested.  Trigger 3: Secretin test: (secretin was injected (0.1 mL/kg body weight) and continuous aspiration of the duodenal contents until the water and bicarbonate output had returned to the initial level) Secretin test : indicated a decreased pancreatic secretory response as manifest by a low level of HCO3- secretion. The patient was prescribed pethidine to control the pain. He was advised to abstain completely from alcohol, and to try to eat regular meals. Subdivisions of the GIT system Alimentary Canal Tube through which food/waste actually passes Mouth, pharynx, esophagus, stomach, small intestine, and Large Intestine Accessory Organs Are connected to alimentary canal –but no food/waste passes through them Teeth, tongue, salivary glands, liver, gallbladder, and pancreas  Gastrointestinal tract (GIT) Sequence of events for digestion and absorption 1) Mechanical homogenization of food and mixing of ingested solids with fluids secreted by the glands of GIT 2) Secretion of digestive enzyme (at least 30g protein per day) that hydrolyses macromolecules to oligomers, dimers and monomers 3) secretion of electrolytes (acid or base) to provide an appropriate environmental for optimal enzymatic digestion 4) secretion of bile acids as biological detergent to solubilise lipids and facilitate their digestion and absorption 5) intestinal final digestion: hydrolysis of nutrient oligomers and dimer by intestinal surface enzyme 6) transport of nutrient molecules from the intestinal lumen across the epithelial cells into blood  Sequence of events for digestion and absorption cont. To accomplish such divers function, the GIT contains specialised glands and surface epithelia: salivary glands, stomach, pancreas, liver, small and large intestine The salivary glands, the gastric mucosa and the pancreas contain specialized cells for synthesis, packing and release of enzymes into the lumen of the GIT (Exocrine) Stomach aids in the digestion through its agitate ability and initiation of protein hydrolysis Pancreas and small intestine are essential for digestion and absorption of all basic nutrients both organ have large reserve capacities e.g. maldigestion due to pancreatic failure becomes a problem only when the pancreatic secretion rate of digestive enzyme drops below 1/10th of the normal rate The surface area of the human intestine is about 180 m2 , a little less than the playing area of a tennis court (195.7m² ) Tennis court (195.7m² )  Overall Fluid Balance of the GI Tract Gastrointestinal secretion Ingestion 2 liters/day Absorption Secretion 8.8 liters/day 7 liters/day Feces 0.2 liter/day  Saliva Saliva is produced by a collection of three major glands Parotid (cheek/jaw) Sublingual (beneath tongue) Submandibular (submaxillary) Saliva is a colorless viscous fluid secreted from the salivary glands A healthy person produces saliva from 1L each day Normally saliva has a pH ranges from 6.0-7.0. Contents of Saliva 1- Water 99% 2- Ions (HCO3-, K+, Cl-, Na+, Phophate, Ca++ 3- Solid proteins 1% a- Mucin (is glycoprotein) the most abundant protein Mucin is responsible for most of saliva’s viscosity. b- Digestive Enzymes Amylase is produced predominantly by the parotid glands Lingual Lipase secreted by von Ebner’s glands Contents of Saliva c- Antibacterial Compounds Muramidase lactoferrin Immunoglobulin IgA d- Epidermal growth factor (EGF) which stimulates gastric mucosal growth e- ABO blood group substances Function of Saliva 1. Lubrication of food - mucins 2. Partial digestion of polysaccharides Salivary alpha amylase like pancreatic amylase, cleaves internal  -1, 4 bonds in starch and can break down up to 50% of starch before being inactivated by gastric acid 3. Partial digestion of Lipid lingual lipase prefers the medium chain triacylglycerid (present in milk), its optimal pH is 4 which allows it to work in the acidic medium of the stomach 4. Moisten mouth and wash away dissolved food (necessary for taste) Function of Saliva 5. Mild antibacterial muramidase, a lysozyme that lyses the muramic acid of certain bacteria (e.g., Staphylococcus) lactoferrin, a protein that binds iron, thus depriving microorganisms of source of iron vital to their growth IgA non-specific antibody that attack bacteria 6. Neutralize acids in food and regurgitated stomach acid 7. Maintenance of teeth – phosphate, Ca2+, fluoride which compensated the demineralization (due to foods fermentation by bacteria). 8. Taste sensation, saliva dissolve the substances that allows the taste buds recognize different flavors.  Control of salivary secretion  Salivary secretion is primarily controlled by the autonomic nervous system and is the only area of the GI tract not regulated by GIT hormones.  Parasympathetic innervation, the predominant control begins in the Salivatory Nuclei of the medulla oblongata (brainstem),  The salivatory nucleus is stimulated by chemoreceptor taste buds, or by conditioned reflex due to activation by smell and/or visualization of food or by mechanoreceptor (chewing ) Atropine, an anticholinergic agent, is a potent inhibitor of salivary secretion. Agents that inhibit acetylcholinesterase (e.g., pilocarpine) enhance salivary secretion.  Salivary secretion is inhibited by sleep, fatigue and fear.  Control of salivary secretion Parasympathetic control blood flow to salivary glands by stimulation induces the acinar cells to release the protease kallikrein, which acts on a plasma globulin, kininogen, to release lysyl-bradykinin, which causes dilation of the blood vessels supplying the salivary glands  Control of salivary secretion The salivary glands are also innervated by the sympathetic nervous system. Sympathetic stimulation tends to result much smaller increase in salivary secretion than parasympathetic stimulation. The increase in salivary secretion observed during sympathetic stimulation is mainly via beta-adrenergic receptors,  Control of salivary secretion Comparing the effect of parasympathetic and sympathetic stimulation on salivary secretion response  The absence of saliva is termed xerostomia (dry mouth). It can be caused by drug side effects, head and neck radiation therapy systemic disease such as Sjögren’s syndrome. The absence of saliva leads to infections, tooth decay and severe discomfort. Stomach The stomach is divided into three regions: Cardia (Cardiac glands) Fundus and body (Oxyntic or parietal, acid- secreting glands) Antrum (Pyloric glands) Stomach mucosa cells  Stomach mucosa cells I. Surface mucous cells: secret neutral insoluble mucins, HCO3- II. Mucous neck cell: secrete soluble mucins, which function as lubricants to the contents of the stomach, HCO3- III. Parietal cell (oxyntic cell): is the most prominent cell type. Secrete H+ and Cl- ions which form HCl in the stomach lumen. secrete gastric intrinsic factor, which is required for the absorption of vitamin B12 in the ileum. IV: Chief cell (Zymogenic cell): secrete digestive enzymes, mainly rennin (in less than 2 years), gastric lipase and, pepsinogen.  Stomach mucosa cells cont. V: Enteroendocrine cells secrete hormones through their basal side for distribution in the blood Endocrine) or affect nearby cells (paracrine). Many different enteroendocrine cells are present in the gastric glands. 1- G cells: make gastrin, which stimulates parietal cells to secrete HCl. 2- EC (enterochromaffin) cells: ≈ 30% make serotonin 3- D cells make somatostatin (inhibits gastrin secretion) 4- ECL (enterochromaffin like) cells produce histamine stimulate HCL secretion  Gastric secretion The fluid secreted into the stomach is called gastric juice Gastric juice is a colorless, watery, acidic, and digestive fluid produced in the stomach. The gastric juice consist from about 99 % Water, and about 1% organic and inorganic substances like electrolytes, hydrochloric Acid, glycoproteins, mucin, intrinsic Factor, enzymes. secreted by many cells in the stomach: A healthy person secretes about 1.5 to 3 liters of gastric juice each day, and has a pH ranges from 1.0 to 3.0.  Function of Stomach (An important function of the stomach is to prepare the chyme for digestion in the small intestine) Storage: acts as temporary reservoir for the meal Secretion of H+ to kill microorganisms and convert pepsinogen to its active form Secretion of intrinsic factor (Glycoprotein binds B12) to absorb vitamin B12 (cobalamin). After binding B12 it binds receptors on ileal absorptive cells and is internalized by endocytosis. Secretion of mucus and HCO3- to protect the gastric mucosa Secretion of water for lubrication and to provide aqueous suspension of nutrients  Function of Stomach Motor activity for mixing secretions (H+ and pepsin) with ingested food Coordinated motor activity to regulate the emptying of contents into the duodenum Absorbs water-soluble and lipid-soluble substances (e.g., alcohol and some drugs like aspirin). Partial protein digestion by pepsin ( optimal pH 2. It is an endopeptidase acting on internal peptide bonds and its products are large peptides called peptones which are potent stimulators of gastrin and cholecystokinin (CCK) release. Partial lipid digestion by gastric lipase (10% of lipid may digested in stomach)  Mechanism of HCl production Alkaline Tide  Alkaline tide A large amount of HCl can be secreted by the parietal cells. This is balanced by an equal amount of HCO3- added to the bloodstream. The blood coming from the stomach during active acid secretion contains much HCO3- , a phenomenon called the alkaline tide. Regulation of HCl Secretion Three factors (gastrin, histamine and Ach (acetylcholine) are important for secreting H+ in large quantities Absence of one factor will be affect the H+ secretion Acid Secretion Is Increased During a Meal  Gastric Mucosal Protection and Defence Gastric Mucosal is protect from the gastric contents (H+ and pepsins) by gastric mucosal barrier i. Mucus gel formation on the luminal surface of the stomach ii. alkaline secretions entrapped within Mucus gel The mucus gel layer is about 0.2 mm thick which effectively separates the HCO3 - - rich secretions of the surface epithelial cells from the acidic contents of the gastric lumen. The mucus allows the pH of epithelial cells to be maintained at nearly neutral despite a luminal pH of about 2. Mucus also slows the diffusion of acid and pepsins to the epithelial cell surface.  Gastric Acid Secretion Is Inhibited by Several Mechanisms The inhibition of gastric acid secretion is physiologically important for two reasons. First, the secretion of acid is important only during the digestion of food. Second, excess acid can damage the gastric and the duodenal mucosal surfaces, causing ulcerative conditions Gastric luminal pH is a sensitive regulator of acid secretion. Proteins in food provide buffering in the lumen; consequently, the gastric luminal pH is usually above 3 after a meal. If the buffering capacity of protein is exceeded or if the stomach is empty, the pH of the gastric lumen will fall below 3. When this happens, the endocrine cells (D cells) in the antrum secrete somatostatin, which inhibits the release of gastrin and, thus, gastric acid secretion.  Gastric Acid Secretion Is Inhibited by Several Mechanisms Acidification of the duodenal lumen Acidification stimulates the release of secretin, which inhibits the release of gastrin, and several peptides, collectively known as enterogastrones, which are released by intestinal endocrine cells. Fatty acids, or hyperosmolar solutions in the duodenum stimulate the release of enterogastrones, which inhibit gastric acid secretion. Gastric inhibitory peptide (GIP), an enterogastrone produced by the small intestinal endocrine cells, inhibits parietal cell acid secretion.  Pancreas Exocrine: – Acini: Secrete pancreatic Insert fig. 18.26 juice. Endocrine: – Islets of Langerhans: Secrete insulin glucagon somatostatin.  Pancreas acini The pancreatic Acini secrete digestive enzymes and large volumes of sodium bicarbonate solution  Pancreas Islet of Langerhans The pancreas, in addition to its digestive functions, secretes 3 hormones: 1. Insulin (Beta cells; 60%). 2. Glucagon (Alpha cells; 25% Insulin and glucagon are crucial for normal regulation of glucose, lipid, and protein metabolism. 3. Somatostatin is secreted by delta cells (form ~10% of islets’s cells).  Pancreatic secretions function The pancreas acts as an exocrine gland by producing pancreatic juice which empties into the small intestine via a pancreatic duct. The pancreas also acts as an endocrine gland to produce insulin, glucagon and somatostatin. It plays an important role 1- in digestion of lipids, proteins, carbohydrates and nucleic acids 2- in metabolism since it produces insulin and glucagon 3- in neutralizing the pH at duodenum to become suitable for the action of the pancreatic digestive enzymes and to prevent damage to duodenal mucosa by acid & pepsin.  Pancreas divisions Exocrine Endocrine Constitute 99% of pancreas. Constitute 1% of pancreas Made of Acinar gland tissue Made of Islets of Langerhans. The cells lining the acini are Secretes: hormones directly into the blood. serous cells containing Secretes 3 hormones: zymogen granules → the 1. Insulin from Beta cells (~60% of Islets cells) precursors of pancreatic 2. Glucagon from Alpha cells (~25%) enzymes (the main source of 3. Somatostatin from Delta cells (~10%) digestive enzymes). Insulin and glucagon are crucial for normal regulation of glucose, lipid, and protein metabolism.  Pancreatic secretions Pancreatic secretions is an alkaline liquid secreted by the pancreas, which contains a variety of enzymes. Composition of pancreatic secretion; 1-. The first component is a electrolytes 2- The second component is the enzymatic component ;which include – Trypsinogen, proelastase, Chymotrypsinogen, Procarboxypeptidase – Pancreatic amylase – Pancreatic lipases, co-lipase, and phospholipase – Deoxyribonucleases and ribonucleases  Composition of Pancreatic secretions Organic materials ( 1 - 2 %) Inorganic materials ( 1 %) Mostly enzymes. Electrolytes. Secreted from: acinar cells. Produced from: the centroacinar & intercalated duct cells. Include: Na+, K+, Ca++, HCO3- ,Cl- with great bulk in form of NaHCO3 HCO3- 5-6 times of plasma Small amount of phosphate, and Mg++ Volume 1-1.5 letter/ day pH: 8.0 -8.3 Pancreatic Enzymes Pancreatic Enzyme activation  Secretion of Bicarbonate Ions From Pancreatic Ductal cell  Bicarbonate Ion Production in Pancreas 1-CO2 diffuses to the interior of the ductal cells from blood and combines with H2O by carbonic anhydrase to form H2CO3 which will dissociate into HCO3- and H+. The HCO3- is actively transported into the lumen. 2- The H+ formed from the dissociated H2CO3 is exchanged for Na+ ions by active transport through blood , which will diffuse or actively be transported to the lumen to neutralize the – ve charges of HCO3-. 3- The movement of HCO3- and Na+ ions to the lumen causes an osmotic gradient causes water to move from blood to ductal cells of the pancreas producing eventually the HCO3- solution. Regulation of Pancreatic Secretion  Regulation of Pancreatic Secretion Secretion of pancreatic juice is stimulated by: Secretin: – Occurs in response to duodenal pH < 4.5. – Stimulates production of HC03- by pancreas. – Stimulates the liver to secrete HC03- into the bile. CCK: – Occurs in response to fat and protein content of chyme in duodenum. – Stimulates the production of pancreatic enzymes. – Enhances secretin.  Intestinal secretions Intestinal juice ; refers to the clear to pale yellow watery secretions from the glands lining the small intestine walls. The glands include; 1- Brunners glands; They are located in the first few centimeters of the duodenum They secrete large amounts of alkaline (bicarbonate) and mucus, in response to (stimulated) by: 1-Irritating stimuli on the duodenal mucosa 2-Vagal stimulation 3- secretin Mucus protects the mucosa secretin “ Stimulus is highly acidic chyme “  Intestinal secretions Intestinal juice ; refers to the clear to pale yellow watery secretions from the glands lining the small intestine walls. The glands include; 2- The Crypts of Liberkuhn, located on the entire surface of the SI Volume: 1800 ml/day. pH: 7.5-8. It participates in the neutralization of acid chyme delivered from stomach. Composition: 1 % inorganic substance electrolytes HCO3, Na, K, etc 0.6 % organic  Intestinal secretions 2- The Crypts of Liberkuhn secretion: 0.6 % organic, Enzymes ; a number of enzymes are present including , peptidase breaks down peptides into amino acids sucrase, maltase, lactase – break down disaccharides into monosaccharides lipase – breaks down fats into fatty acids and glycerol enterokinase – converts trypsinogen to trypsin Hormones somatostatin – hormone that inhibits acid secretion by stomach cholecystokinin – hormone that inhibits gastric glands, stimulates pancreas to release enzymes in pancreatic juice, stimulates gallbladder to release bile secretin – stimulates pancreas to release bicarbonate ions in pancreatic juice  Regulation of intestinal secretion Brunner's glands Intestinal juice Secretion is stimulated by: Secretion is stimulated by : -Secretin (Hormonal) 1.Distension, irritating stimuli and -Tactile (Mechanical) vagal stimulation. -Vagal stimulation(Neural) 2.Hormones : -Gastrin , Secretin, CCK, glucagons, enterocrinin. Sympathetic system inhibits the intestinal secretion.  Bile secretion It is a watery mixture of organic and inorganic compounds. It is synthesized in the liver. It passes into the duodenum through common bile duct. Or it can be stored in the gall bladder when not needed for the digestion. Bile secretion  Composition of Bile Bile from the liver has about 97% water and 3% solids. Organic substance: Inorganic substance: 1. Bile salts 1. Na 2. Mucin 2. Cl 3. Bile pigments 3. HCO3 4. Lipids( lecithin, neutral fats, 4. K fatty acids, cholesterol) 5. Ca palmitate pH 7.8-8.6 Amount secreted / day is 0.5 – 1 liter  Functions of Bile Salts Bile salt (bile acids ) is synthesized from cholesterol Four primary physiologically significant functions: 1. They facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases. 2. Elimination of excess cholesterol is converted into bile salts and subsequent excretion in the feces which represent the only significant mechanism for the Elimination of cholesterol 3. They facilitate the intestinal absorption of fat-soluble vitamins. 4. bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder.  Changes in Composition Bile is stored in the gall bladder and during this time changes occur in its composition: 1. The capacity of gall bladder is only 50 ml. a. To store large amounts of bile, the gall bladder wall absorbs water and concentrate the bile 5- 10 times. b. Water and inorganic salts are absorbed through the lymphatic and blood vessels of the wall of gall bladder. c. Na comes out of the gall bladder, and H goes inside. d. There H combines with HCO3 and formsCO2 and H2O. e. In this way the bile either becomes neutral or acidic. f. Acidic pH is important because this prevents the precipitation CaCO3 which can initiate gall stone formation. g.Other substances secreted by the wall of the gall bladder include toxins, drugs, copper and zinc.  Regulation of Biliary Secretion Choleretics: These are the substances that increase the secretion of bile by the liver. 1.Bile salts are the most powerful choleretics. 2.Salicylates also increase the secretion. 3.Ingestion of food (Bile salts). 4.Hepatocrinin- hormone of duodenal origin. 5.Secretin (HCO3). 6.Gastrin & CCK. 7.Vagus nerve stimulation.