Gastrointestinal Flashcards
(94 cards)
1
Q
Which are the retroperitoneal organs?
A
S- Suprarenal (adrenal glands)
A- Aorta + IVC
D- Duodenum (2nd and 3rd segments)
P- ancreas
U- ureters
C- Colon (Ascending and descending)
K- Kidneys
E- Esophagus
R- Rectum
2
Q
Differences between the jejunum and ileum
A
The ileum has peyer’s patches
The jejunum has a thicker intestinal wall than the ileum
Jejunum has longer vasa recta than the ileum
The jejunum has less arcades than the ileum
3
Q
Differences between the small and large intestine
A
Small intestine has villi. Large intestine doesn’t
Small intestine is narrower whilst the large intestine is wider
Large intestine has epiploic appendages.
Large intestine has haustrations
Small intestine has plicae circulares
Small intestine has peyer’s patches
4
Q
What is the epithelial change caused by barrett’s esophagus?
A
Metaplasia occurs
Stratified squamous non keratinising epithelium to simple columnar epithelium
5
Q
How much saliva is produced in a day?
A
800ml - 1500ml
6
Q
What is the function of saliva?
A
Lubrication to aid in swallowing
Helps with mouth hygiene and to protect it against bacteria
Digestion - Amylase breaks down starch in the mouth
7
Q
What type of salivary secretions do the 3 main salivary glands secrete?
A
Parotid- Serous secretions
Submandibular- Mixed (serous and mucous)
Sublingual- Mucous secretions
8
Q
Which is the biggest/main continuously secreting salivary gland?
A
Submandibular
(Sublingual also continuous but is smaller. Parotid is not continuous, must be stimulated by cephalic phase)
9
Q
What kind of saliva do the minor salivary glands secrete?
A
Mucous except for Von Ebner gland which is serous secreting
10
Q
Difference between serous and mucous secretions of salivary glands
A
Serous - Contains water and alpha amylase
Mucous- Contains water and mucus
Serous- Histologically dark
Mucous- Histologically pale (mucus)
Serous- Has a small central duct
Mucous- Has a large central duct
11
Q
What are the layers of the connective tissue/muscle of the intestines
A
Lumen, epithelium, Basement membrane, Lamina propria, Muscularis mucosa, submucosa, Inner circular layer (muscular propria), outer longitudinal layer (muscularis propria), adventitia/serosa
12
Q
What are the plexus that arise from the enteric nervous sytem? Where are they located?
A
Submucosal plexus - located in submucosa
Myenteric plexus - Between the outer longitudinal and inner circular smooth muscle layers of the intestine
13
Q
How does the layers of tissue and muscle in the stomach differ from that of the intestines?
A
Stomach has an innermost oblique layer, middle circular layer and outer longitudinal layer
14
Q
How is the gastric mucosa protected?
A
- It (foveolar cells) produces alkaline mucus which acts as a buffer
- It has tight junctions between cells to prevent the entry of acid
- Stem cells at the base of gastric pits produce new cells to replace damaged cells
- Negative feedback loops which prevent the overproduction of HCl e.g. H+ stimulates somatostatin which in turn inhibits parietal cell activity
15
Q
Which cell secretes pepsin?
A
NONE. Chief cells secrete pepsinogen which is converted to pepsin by HCl
16
Q
What are the functions of the stomach?
A
- Storage and digestion of food
- Activates enzymes (pepsinogen –> pepsin)
- Secretes intrinsic factor which is required for absorption of vitamin B12
- Produces HCl which creates an acidic environment that kills microbes
17
Q
What are the actions of the parietal cell?
A
- Carbonic anhydrase equation
HCO3- leaves the cell into the blood and is exchanged with Cl- via an anion exchanger. (basolateral- non lumen side) - The Cl- passively diffuses into the stomach lumen via an ion channel. (Cl- + H+ –> HCl)
H+ leaves the cell into the stomach lumen via a hydrogen potassium ATPase pump. K+ enters the parietal cell via this way.
K+ also passively diffuses back into the stomach lumen down its concentration gradient via an ion channel (to maintain electrical stability and neutrality)
18
Q
In what proportion is gastric acid produced in the cephalic and gastric phase? Describe each phase
A
Cephalic - 1/3
Gastric- 2/3
Cephalic- The sight, smell, taste, thought and chewing of food stimulates the brain to stimulate the stomach via the vagus nerve, thus producing gastric acid before the food enters the stomach. Via the release of acetylcholine from parasympathetic nerve fibres.
Gastric- Gastric distension (detected by stretch receptors), presence of peptides and amino acids (proteins)
Stretching of the stomach wall results in stretch receptors stimulating the vagus nerve to release acetylcholine, thus triggering HCl production
19
Q
Where is acetylcholine released from and what is its function in relation to digestion?
A
Acetylcholine- From vagus nerve via cephalic and gastric phases - thought, distension of stomach, etc
- Binds to parietal cells increasing upregulation of hydrogen pumps
- Binds to G cells increasing gastrin secretion
- Binds to D cells to inhibit somatostatin secretion
- Binds to enterochromaffin like cells to secrete histamine
- Binds to chief cells to promote release of pepsinogen
20
Q
Where is gastrin released from and what is its function?
A
Gastrin- From G cells via acetylcholine
- Binds to parietal cells to increase upregulation of hydrogen pumps
- Binds to chief cells to cause vesicular fusion (via calcium) and release of pepsinogen via exocytosis.
- Binds to enterochromaffin like cells to cause the release of histamine
21
Q
Where is Histamine released from and what is its function?
A
Histamine- From enterochromaffin like cells (mast cells) via acetylcholine and gastrin
- Binds to parietal cells to cause the upregulation of hydrogen pumps
22
Q
Where is somatostatin released from and what is its function?
A
Somatostatin- From D cells when pH is low
- Binds to g cells to inhibit gastrin production
- Binds to parietal cells to inhibit hydrogen pumps
- Also inhibits TSH, cortisol and growth hormone
23
Q
Where is secretin released from and what is its function?
A
Secretin- From S cells in the presence of fatty acids
- Binds to antral g cells to inhibit gastrin production
- Stimulates hepatocytes to convert cholesterol into bile which moves through the sphincter of oddi into the duodenum
- Binds to epithelial cells in the pancreas, stimulating them to secrete bicarbonate ions
24
Q
Where is cholecystokinin released from and what is its function?
A
Cholecystokinin- From I cells in the presence of fatty acids and amino acids
- Binds to parietal cells to inhibit hydrogen pumps
- Can bind to receptors on the liver to enhance the action of secretin which stimulates bile synthesis
- Can bind to receptors on the gallbladder stimulating contraction
- Can bind to receptors on the sphincter of oddi, stimulating the relaxation of the sphincter
- Can bind to acinar cells in the pancreas to stimulate fusion of vesicle containing zymogens (inactive enzymes) with the cell membrane to be secreted into the duodenum.
- It can also delay gastric emptying by inhibiting the contraction of the pyloric sphincter
25
What are the enterogastrones released in the small intestine during the intestinal phase of digestion?
Secretin and cholecystokinin
26
What happens in the intestinal phase of digestion to decrease gastric acid production?
- Duodenal distension, low luminal pH (from acidic chyme) and presence of amino acids and fatty acids cause a decrease in gastric acid production.
- Fatty acids stimulate duodenal S cells to secrete secretin into the blood which inhibit G cells, thus inhibiting secretion of gastrin. S cells also promote somatostatin release (inhibiting G cells)
- The presence of fatty acids and amino acids also stimulate enteroendocrine I cells to secrete cholecystokinin which bind to parietal cells to inhibit the Hydrogen pump. (cholecystokinin also causes gallbladder contraction to stimulate bile release)
27
What are peptic ulcers? What is it caused by?
- An ulcer in breach in a mucosal surface (epithelium has been stripped away from a part of a tissue).
- It is caused by helicobacter pylori infection (lives in gastric mucus and leads to inflammatory response), - treat with proton pump inhibitors
- Drugs like NSAIDS (aspirin, ibuprofen)- affects synthesis of prostaglandins (inhibits Cox-1) which reduce gastric mucus production → essentially mucous secreting cells are stimulated by prostaglandins.
-Chemical irritants like alcohol
- Gastrinoma - neuroendocrine tumours that secrete gastrin with resultant excessive gastric acid production.
(caused by excess gastric acid production or decreased mucosal defense)
28
What are 2 drugs that can be used to reduce gastric acid secretion?
H+ inhibitors- omeprazole
H2 receptor antagonist- Ranitidine
29
At what pH will pepsinogen be activated? So what is activation regulated by?
Pepsinogen is converted to pepsin (active form) between pH 1.8 - 3.5. Best pH is less than 2.
Pepsin can also digest pepsinogen into pepsin in a positive feedback loop.
Pepsinogen activation is thus regulated by gastrin and pH
30
What is the function of pepsin? How many percent of protein digestion takes place in the stomach?
Pepsin can also digest pepsinogen into pepsin in a positive feedback loop.
Pepsin also breaks down proteins into peptides in the gastric lumen (with help from HCl) - 20% of protein digestion
Pepsin chemically shreds meat into smaller pieces with greater surface area for digestion
31
What is the process of gastric motility?
- Peristaltic waves in the gastric body (as a result of the enteric nervous system). There is weak contraction when the stomach is empty (otherwise waste of energy) but with more food and distension of the stomach, the strength of the contractions increase leading to mixing.
There is more powerful contraction in the gastric antrum (stronger it is, the further it travels down the stomach) and the pylorus closes as peristaltic waves reach it.
As the pylorus is closed, little chyme enters the duodenum and antral contents are forced back to the body of the stomach (mixing)
32
What is the frequency of peristaltic waves in the stomach and what is it determined by?
Pacemaker cells in the muscularis propria. Interstitial cells of cajal . (3 contractions/min) TAKE NOTE
- Located in the greater curvature of the stomach
The pacemaker cells are constantly but slowly depolarising and repolarising (cycle)
The signals (action potentials) are transmitted via gap junctions to adjacent smooth muscle cells
33
How is gastric emptying regulated?
Gastric contents in the duodenum (which lowers pH, increases fatty acids and increases amino acids, duodenal distension) cause an increase in secretion of enterogastrones such as secretin and cholecystokinin and also stimulates short and long neural reflexes.
Secretin, cholecystokinin and short neural reflexes via enteric neurons cause decreased gastric emptying (local response- enteric nervous system)
Long neural reflexes decrease parasympathetic
stimulation and increase sympathetic stimulation thus decrease gastric motility and emptying. (CNS response)
34
Why do we need to be able to control gastric emptying? What happens without being able to control it?
The stomach is much larger than the duodenum
Overfilling of the duodenum with a hypertonic solution (gastric contents- hypertonicity can draw a lot of water into the duodenum) can cause dumping syndrome which presents with vomiting, bloating, cramps, dizziness, sweating, diarrhoea
Duodenal overfilling will result in outpouring of fluid through the wall of the duodenum into the lumen.
35
What can enhance gastric motility and what is enhanced gastric motility?
An increase in the strength/frequency of contractions of the muscle of the stomach wall. (frequency helps to move food and other substances quickly through the digestive system and strength helps to break down food more efficiently)- strength is more important here.
Excitatory neurotransmitters and hormones like gastrin can enhance gastric motility
36
What can cause a decrease in gastric motility and what is decreased gastric motility?
Decreased gastric motility is when the contractions of the muscles of the stomach are weaker.
This is due to: duodenal distension, increased duodenal luminal fat, decreased duodenal luminal pH, increased sympathetic nervous system stimulation and decreased parasympathetic nervous system stimulation
37
What is the total amount of water in the GI over 24 hours?
How many percent is reabsorbed and where is it mostly reabsorbed?
9000ml per day
7000ml secreted (1000 intestines, 1500 saliva, 2500 stomach, bile 500, pancreas 1500)
2000ml ingested
98% of this is reabsorbed (8800ml - mostly in jejunum, followed by ileum then colon)
Just roughly know
38
What is the most abundant ion in chyme?
Sodium
39
What vitamins are mainly absorbed in the duodenum, jejunum and ileum?
Duodenum- Iron
Jejunum- Vitamin B and C (excluding B12)
Ileum- Vitamins A, D, E , K and vitamin B12
40
Where does carbohydrate digestion happen?
- Alpha amylase in the saliva breaks down starch in the mouth
- Pancreatic amylase in the duodenum (through major duodenal papilla) breaks down the starch into oligosaccharides or disaccharides -- 95% of starch digestion
- As the oligosaccharides and disaccharides move through the duodenum to the jejunum, they are broken down into monosaccharides (glucose, galactose, fructose)
41
How are monosaccharides absorbed in the intestine?
Glucose and galactose by secondary active transport with sodium (Co-transport)-- SGLT-1 (sodium dependent glucose transporter)
Fructose- facillitated diffusion by Glut-5
All of them leave the small intestinal cells into the blood via Glut 2 transporters (after moving into the cells from the lumen as mentioned above) --> they travel to the liver via the portal vein.
42
How is glucose different in the absorptive and postabsorptive state?
Absorptive state (eaten)---- glucose is taken up by the liver and stored as glycogen. (also stored in skeletal muscle)
Post absorptive state (fasted)- glycogen stores are broken down and used as glucose by the skeletal muscles
43
How are proteins digested and absorbed?
Digestion
Stomach- pepsin cleaves bonds between proteins, and shreds meat
Duodenum- pancreatic peptidases (chymotrypsin) --> typically secreted as zymogens (converted to active form in duodenum) aid in protein digestion.
Absorption
Protein is absorbed via secondary active transport with sodium. And then into the interstitial fluid and systemic circulation
44
What is the process of fat digestion? What is the process of fat absorption?
- Starts in the mouth
- In the duodenum, bile emulsifies fat (bile salts prevent the fat droplets from reaggregating)
- Lipase breaks down triglycerides into monoglyceride and 2 fatty acids
- The monoglyceride and fatty acids are packaged into micelles (in the small intestine lumen), then transported to and released at the intestinal brush border.
Absorption
- When the contents of the micelles are released at the intestinal brush border, they enter the small intestine cells and the monoglyceride and fatty acids (re)aggregate (to triglycerides) in the smooth endoplasmic reticulum.
- The triglycerides are packaged into vesicles with cholesterol and is modified by the golgi apparatus to form chylomicrons
- Chylomicrons are then released into the lymphatic system via lacteals and enter the bloodstream for transport to various tissues in the body
45
Function and source of Vitamin A
Where is it stored?
What does deficiency lead to
Retinol/rhodopsin/caretonoids
It is important for vision
It is stored in Ito cells in the liver.
Source: Spinach, Carrot, liver, milk, eggs
Deficiency- (night blindness)
46
Function and source of vitamin D
Calciferol
- Regulates amount of calcium and phosphate in the body
(stored in adipose tissue)
Source- UV light, fish, red meat, liver
Deficiency- osteomalacia, rickets
47
Which are the fat soluble and water soluble vitamins?
Water soluble - B and C
Fat soluble- A, D, E and K
48
Function and source of E?
Where is it stored?
- It acts as an antioxidant and scavenges free radicals (reactive oxygen species- speeds up ageing process of the body) - can damage DNA
Stored in the liver
Source- Nuts, seeds, vegetable oil
49
Function and source of vitamin K
Where is it stored?
What does a deficiency result in?
- Helps to make clotting factors 10,9,7,2
Stored in the liver
Deficiency results in- Bleeding disorders
Source- spinach, broccoli, vegetable oil, lettuce
Synthetic- K3 and K4
50
Function and source of Vitamin B12
Helps to synthesise DNA
Helps with red blood cell formation
Intrinsic factor aids in the absorption of vitamin B12
Stored in the liver
Source - Fish, meat, milk, eggs
Deficiency- can lead to pernicious anaemia
51
Function and source of vitamin C
Aids in the absorption of iron, boosts the immune system, helps with maintaining cartilage, bones and teeth
Source- citrus fruits, tomato, potato
Deficiency- scurvy
52
Describe iron metabolism
Do females or males lose more iron?
How is it transferred and stored?
Iron metabolism- females lose more than males (due to menstruation) but overall humans are good at conserving iron and keeping it within our body.
On average, we take in 1-2mg of iron per day through our diet.
This iron is absorbed into our blood plasma and is transported via plasma transferrin.
Iron can be transported to the muscle to produce myoglobin, can be transported to bone marrow to make red blood cells, excess iron is stored in the liver and reticuloendothelial macrophages as ferritin.
53
What are 2 minerals stored in the liver?
Iron and copper
54
What is the formula for BMI?
What are the values for overweight and obesity?
weight/height squared
25- overweight
30- obese
35 and above- extremely obese
55
What are the functions of the liver?
- Carbohydrate and fat metabolism
- Protein synthesis- albumin, clotting factors
- Storage (stores glycogen, vitamins and minerals)
- Bilirubin metabolism and excretion
- Detoxification of xenobiotics
- Bile production
- Involved in immune responses- it has kupffer cells which help to phagocytose bacteria (reticuloendothelial system)
56
What do complement proteins synthesised by the liver do?
- Opsonisation (process of recognising and targeting invading particles for phagocytosis)
- Phagocytosis
- Inflammation
- Lysis
57
What is gluconeogenesis?
When does it happen?
The pathway by which glucose is formed from non-hexose precursors such as glycerol, lactate and pyruvate. (essentially reversal of glycolysis)
It happens about 8 hours after fasting when glycogen stores in the liver start to deplete and an alternative source of glucose is required.
58
Briefly explain the glucose alanine cycle
Increased activity or exercise cause muscle cells to break down glucose through glycolysis to produce pyruvate. (additionally, amino acids are broken down into alpha ketoacids and ammonium)
IN THE MUSCLES (transamination)
Pyruvate is converted to → alanine via the transfer of an amino group from glutamate. (transamination- via alanine aminotransferase)
Glutamate → alpha ketoglutarate after donating its amino group (oxidative Deamination by glutamate dehydrogenase)
Alanine is transported to the liver through the blood
IN THE LIVER
Alanine aminotransferase catalyses the transfer of the amino group from alanine to alpha ketoglutarate forming pyruvate and glutamate
(Transamination)
(alanine → pyruvate, alpha ketoglutarate → glutamate)
Pyruvate used for gluconeogenesis (can also form lactate and undergo glycolysis) - glucose can be used again by muscle cells
Glutamate undergoes oxidative deamination to get rid of ammonia via the urea cycle
glutamate + H2O → alpha ketoglutarate and NH4+ - catalysed by glutamate dehydrogenase
– essentially this cycle, while producing more ATP, it also gets rid of ammonia as urea via the urea cycle
59
Briefly explain the urea cycle
In the liver, glutamate is oxidised and the ammonia group is removed (does it form alpha ketoglutarate again?)
In the mitochondria of hepatocytes, ammonia and CO2 (+ ATP) form carbamoyl phosphate (catalysed by carbamoyl phosphate synthetase
Carbomoyl phosphate + ornithine —> citrulline (catalysed by ornithine transcarbamylase)
Citrulline + aspartate —> argininosuccniate (catalysed by argininosuccinate synthetase)
Argininosuccinate releases fumarate —> arginine (catalysed by argininosuccinate lyase)
Arginine + water results in the release of urea —> ornithine (catalysed by arginase)
Urea enters the bloodstream, is filtered by the kidneys and is excreted as urine.
60
How many peptide bonds does a protein and polypeptide have?
Protein-- more than 50 peptide bonds
Polypeptide less than 50
61
What is the transamination of amino acids?
Transferring an amino group from an amino acid to a alpha keto carboxylic acid
Alanine + alpha ketoglutarate --> Pyruvate + glutamate (alanine aminotransferase catalyses the reaction) REVERSIBLE REACTION
62
What is the oxidative deamination of amino acids?
The breaking down of amino acids for energy (alpha ketoglutarate which is used in the krebs cycle is produced, but NH3 (ammonia) is also produced and it gets excreted via urea cycle
Glutamate + H2O --> alpha ketoglutarate + NH3 (catalysed by glutamate dehydrogenase)
63
Where are lipids stored?
Adipocytes (mainly white, some brown)
Also stored in the liver
64
Key functions of lipids
- Absorption of fat soluble vitamins
- Can act as an insulating layer and provide thermal regulation
- Synthesise various hormones
- Cushioning and shock absorption
- Structural component of cell membrane
- Energy storage, they provide 9kcal/g of lipid
65
Key functions of amino acids
- Protein synthesis
- Synthesis of enzymes
- Energy production 4kcal/g of protein
- Synthesis of hormones
- Immune system function- as they aid in production of antibodies
66
What are HDLs, LDLs, VLDLs,
High density lipoproteins carry excess cholesterol back to the liver for disposal (reducing blood cholesterol levels) -- Synthesised in the liver
Low density lipoproteins carry cholesterol from the liver to the cells (raising blood cholesterol levels) - synthesised in the liver
Very low density lipoproteins- Transport triglycerides synthesised in the liver to adipose tissue (through blood)
(Intermediate density lipoproteins - are intermediates of VLDLs and are converted to LDLs)
67
What is the beta oxidation of fats? Where does it occur?
Beta oxidation is a metabolic process in which fatty acids are broken down in the mitochondria to generate acetyl CoA, NADH and FADH2. (acetyl CoA used in the citric acid cycle and the latter 2 are used in the electron transport chain.)
It can occur in the mitochondria (only beta oxidation), the peroxisome (alpha and beta oxidation) and endoplasmic reticulum (Omega oxidation)
68
What is the rate limiting step of fatty acid oxidation?
Carnitine shuttle
69
How long does a fatty acid chain have to be for the carnitine shuttle to bring it into the mitochondrial matrix?
more than 12 carbons
70
How many percent of of the body's ATP is produced by beta oxidation of fatty acids?
60% (krebs cycle about 15%)
71
Describe fatty acid oxidation
1. Lipase breaks the bonds of triglyceride molecules releasing free fatty acids.
2. The fatty acids move into target cells via the protein, fatty acid transporter.
3. The fatty acid is activated to form acyl adenylate - this process requires ATP. And it is then converted to Acyl CoA, catalysed by Acyl-CoA synthetase. (In the cytoplasm)
4. Acyl CoA + carnitine —> acyl carnitine (carnitine palmitoyl transferase 1)
5. Coenzyme A is added to the acyl carnitine molecule at the inner mitochondrial membrane forming acyl CoA and the carnitine molecule is transferred back to the inter membrane space.
In the mitochondrial matrix 4 reactions (oxidation, hydration, oxidation, thiolysis)
1. Acyl CoA —> Enoyl CoA — by Acyl CoA dehydrogenase — a double bond is formed between the alpha and beta carbons
2. Hydroxyl group is added to enoyl CoA (in the form of water) —> Hydroxyacyl CoA —— by Enoyl-CoA hydratase
3. Hydroxyacyl CoA —> keto acyl CoA by hydroxyacyl CoA dehydrogenase — carbonyl group is added
4. Ketoacyl CoA is more symmetrical, it is split into 2 molecules by thiolase to form a fatty acid chain that is 2 carbons shorter and an acetyl CoA molecule (the fatty acid chain undergoes the reaction again.
72
What are the differences between peroxisomal beta oxidation and mitochondrial beta oxidation?
Peroxisomal beta oxidation
Mitochondrial beta oxidation
Carried out in peroxisomes and involves specific enzymes present only in peroxisomes
Carried out in the mitochondria - carried out by different enzymes from peroxisomal beta oxidation
Does not produce ATP directly
Produces ATP directly through oxidative phosphorylation
Generates hydrogen peroxide as a byproduct (a reactive oxygen species) - can lead to DNA damage
Does not generate hydrogen peroxide
Metabolises very long fatty acid chains that are too large to enter the mitochondria (until 10 carbon chain)
Metabolises only medium to long fatty acid chains that are able to enter the mitochondrial matrix through the carnitine shuttle.
73
When there is excess Acetyl CoA, what happens? What are the steps?
Ketogenesis (can also be used for lipogenesis (fatty acid synthesis)
1. 2 x acetyl CoA —> Acetoacetyl CoA (by thiolase)
2. Acetoacetyl CoA —> HMG CoA (by HMG-CoA synthase)
3. HMG CoA —> Acetoacetate (by HMG-CoA lyase4
4. Acetoacetate —> Acetone(decarboxylation) or beta-hydroxy butyrate (betahydroxybutyrate dehydrogenase)
74
What is the most common buffering system?
The carbonic anhydrase reaction (carbonic anhydrase catalyses the bidirectional conversion of carbon dioxide and water into bicarbonate
75
What are xenobiotics? How do they enter the body?
They are foreign substances that don’t have nutritional value and serve no purpose, and thus are excreted. They can be toxic if they are not excreted in time (as they may be harmful to cells by damaging cell protein, lipids or DNA)
Xenobiotics enter via the diet and via medications. We can potentially breathe them in.
They are rendered safe via detoxification and are disposed off as waste.
They react with O2 and release free radicals
76
What happens in phase 1 of xenobiotic detoxification?
In phase 1 of xenobiotic detoxification, Cytochrome P450 and enzyme present in the smooth endoplasmic reticulum in the liver modifies the chemical structure of the xenobiotic through non synthetic reactions such as: oxidation (hydroxylation, deamination), reduction (hydrogen addition) or hydrolysis (splitting of amide or ester bonds) reactions. (Oxidation increases the polarity of the substance slightly to make it more water soluble (slightly polar), to make it easier to eliminate from the body and easier to be transported in blood). Overall Phase 1 prepares the xenobiotic for further processing and elimination from the body.
77
What is cytochrome P450 (some characteristics)and what are 2 important types of this enzyme?
Cytochrome P450 is present in the smooth endoplasmic reticulum in the liver.
They have a cytochrome reductase subunit which uses NADPH to transfer hydrogen to CYP450 to reduce it, activating CYP450 and allowing it to carry out its function.
They oxidise substrates and reduce oxygen
They are inducible- enzyme activity may be increased upon exposure to certain molecules
They generate a reactive free radical
CYP3A4 is a member of the Cytochrome P450 family that is responsible for metabolizing about 50% of all prescription drugs.
CYP2D6 is a member of the Cytochrome P450 family that is primarily expressed in the liver. (polymorphism-existing in different forms- ordinary drug dose can either result in adverse drug reactions or no drug response) Depending on how fast a patient metabolises, CYP2D6, they would require different dosage of drugs (you can’t give the same amount of codeine to 2 different people who metabolise it differently) too much and it would be dangerous.
CYP2E1 - metabolises ethanol
78
What is the mechanism of the action of the cytochrome reductase subunit attached to cytochrome P450? What are the products of this mechanism?
Cytochromes contain a haem component which is capable of oxidising molecules (via OH addition) by becoming reduced themselves.
The reductase uses NADPH to become active and reduce the Cytochromes to allow oxidation of the foreign molecule
The products are water and a free radical
79
What happens in phase 2 of xenobiotic detoxification?
Phase 2- The modified foreign substances produced from phase 1 are conjugated with molecules such as glucuronic acid, sulfate, glutathione, etc (via covalent bonds). This modification makes them much more hydrophilic and polar, and less toxic, thus they are easier to eliminate from the body. Enzymes such as UDP- glucuronosyltransferase, sulfotransferase, etc catalyse the conjugation reactions. Overall, phase 2 reactions are biosynthetic and are involved in conjugation to produce hydrophilic metabolites.
Conjugation with glucuronic acid is called glucuronidation. With sulfate is called sulfation
After phase 2, the detoxified xenobiotic is excreted
80
What happens as a result of the actions of alcohol dehydrogenase and cytochrome 2E1?
When alcohol dehydrogenase converts ethanol into acetaldehyde, there is an increased production of NADH which is taken to the electron transport chain to help produce more ATP. Increased production of ATP will inhibit the Krebs cycle and the acetyl CoA supposed to be used in the Krebs cycle is used in fatty acid synthesis instead, leading to an increased fatty liver.
When Cytochrome 2E1 converts ethanol into acetaldehyde, from the cytochrome system, reactive oxygen species are produced which could lead to DNA, protein and enzyme damage.
Acetaldehyde can bind to gluthathione, predisposing it to damage by hydrogen peroxide and other free radicals (it essentially takes up the free radicals so the free radicals don’t damage DNA and proteins)
Lastly, acetaldehyde can also contribute to alcohol induced hepatitis (via triggering of the immune system and lymphocytes) - liver inflammation and damage
81
Example of inducible cytochrome
Example of inhibited cytochrome
Cytochrome CYP1A2 can be induced by smoking,
Cytochrome CYP3A4 can be inhibited by grapefruit juice,
82
What are the constituents of bile?
Bile salts
Cholesterol
Xenobiotics
Electrocytes
Bilirubin
Phospholipids
83
Passage of biles from hepatocytes
Bile canaliculi --> bile ductules --> right and left hepatic ducts --> common hepatic duct --> common bile duct --> joins with pancreatic duct at the hepatopancreatic ampulla
84
What is the enterohepatic circulation and how much of the bile acids are reabsorbed?
Where are they reabsorbed?
It is the process of recycling substances such as bile acids, bilirubin and more between the liver and the small intestines.
95% of bile acids are reabsorbed (10%-20% urobilinogen)
Typically in the terminal ileum into the portal vein.
85
How many enterohepatic circulations per meal?
2-3
86
What happens to bile during the Fed and fasted state?
Fasted state- Bile acids travel down the biliary tract to the gallbladder where it is concentrated 10 fold
Fed state- CCK is released (from duodenal mucosa) and stimulates contraction of the gallbladder and relaxation of the sphincter of oddi to allow bile to flow into the duodenum.
87
Describe bilirubin metabolism
Haemoglobin is broken down into heme and globin (globin is broken down into amino acids which can go to the bone marrow to form more haemoglobin)
Heme is converted to biliverdin via heme oxygenase (from kupffer cells)- releases iron
Biliverdin is converted into unconjugated bilirubin (not water soluble) via biliverdin reductase
Unconjugated bilirubin binds to albumin and is then taken up by the liver via bilirubin transporter
Unconjugated bilirubin is taken to the smooth endoplasmic reticulum. Where it undergoes glucuronidation (glucuronosyltransferase binds a glucuronic acid to the unconjugated bilirubin) (making it more water soluble)
The conjugated bilirubin is released from the liver cell into the biliary system → So when bile flows into the duodenum, it follows into the intestine.
Conjugated bilirubin is hydrolysed by bacteria (glucuronic acid is removed) to form urobilinogen (which is either recycled via the Enterohepatic circulation 10%) or oxidised to form stercobilin (80%)
A small amount of urobilinogen is bound to albumin and is excreted in the urine 10% (via the kidneys) → BUT when urobilinogen is oxidised to form stercobilin, it is excreted in the stool
Last.2 steps are in terminal ileum
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What are the exocrine and endocrine secretions of the pancreas?
What does the paracrine factor secreted by the delta cells of the pancreas do?
Exocrine
Acinar cells produce inactive enzymes - trypsinogen and chymotrypsinogen (activated at the brush border of enterocytes in the duodenum)
Duct cells - secrete bicarbonate
Endocrine
Beta cells- insulin
Alpha cells- Glucagon
Delta cells- somatostatin (inhibits glucagon and insulin production)
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Functions of insulin
- Promotes uptake of glucose into cells particularly muscle, the liver and fat cells.
- Glycogenesis - stimulates conversion of excess glucose into glycogen
- inhibits gluconeogenesis- production of glucose - to prevent excess glucose production
- Decreases fatty acid oxidation
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Functions of glucagon
- Stimulates glycogenolysis--> break down of glycogen stores
- Stimulates lipolysis --> break down of stored fats released fatty acids into the blood stream for energy production
- Inhibits glycogenesis
- Promotes ketogenesis
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What is pre-hepatic jaundice (haemolytic)
Which type of bilirubin will have raised levels?
What are its causes?
The excess production of bilirubin due to excess haemolysis → Production of bilirubin overtakes the ability of the liver to conjugate the bilirubin
Unconjugated bilirubin levels are raised
Causes: Inherited blood conditions like sickle cell anaemia, autoimmune conditions
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What is hepatic jaundice? (hepatocellular)
Which type of bilirubin will have raised levels?
What are its causes?
Occurs due to liver failure/disease and the bilirubin is unable to leave the liver cells and is thus not able to be excreted.
(hepatocytes are damaged) - unconjugated bilirubin uptake is impaired, conjugated bilirubin secretion is impaired
Both unconjugated and conjugated bilirubin will be increased
Amber/dark urine
Causes: Viral hepatitis, liver cirrhosis
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What is post-hepatic jaundice? (cholestatic)
Which type of bilirubin will have raised levels?
What are its causes?
Signs in the stool/urine
- Damage to the billiary system obstructing the flow of bile
Levels of conjugated bilirubin are raised
Causes: Gallstones, Pancreatic carcinomas, carcinoma of ampulla of vater
Pale and fatty stools
Dark urine- the conjugated bilirubin diffuses into the blood and circulates and is excreted causing dark urine
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borders of calot's triangle
cystic duct, common hepatic duct, inferior surface of the liver
