Metabolic Functions of the Liver

Question 1

What relevance is the positioning / functioning of the liver in the body?

Answer 1

• The liver is the first major organ in line from the gut. Therefore, it can handle large amounts of newly absorbed nutrients.
• It is positioned between the gut and the heart; therefore, it ‘protects’ major vessels from direct contact with dietary nutrients, etc.
• It empties directly into the major vessel entering the heart, ensuring the rapid circulation of its products.
• The bile ducts empty directly into the gut, meaning that they can rapidly influence the digestive process.

Question 2

How is the liver important in maintaining constant blood glucose levels after a meal?

Answer 2

• The liver removes the glucose from the blood after a meal.
• It stores the glucose in the form of glycogen (as it is readily accessible).
• [The other energy reserve is triglycerides that are stored as VLDL in adipose tissue and muscles].
• In order to restore blood glucose levels it can perform glycogenolysis and gluconeogenesis.
• It regulates the fluxes (continuous changes) through glycolysis, gluconeogenesis and the pentose phosphate cycle.

Question 3

What is the importance of the liver for protein and amino acid metabolism?

Answer 3

1. The liver is the major site for the synthesis of many serum proteins, such as albumin and the blood clotting factors.
2. The liver degrades excess amino acids, particularly during gluconeogenesis.
   
   • Glucogenic amino acids ——-> sugars.
   • Ketogenic amino acids ——–> ketone bodies.
     
     • Both of these products can be used as a energy source for non-hepatic tissues.
3. The liver is the major site for transamination and deamination of amino acids, and for the detoxification of ammonia.

Albumin meaning - It is a simple form of protein that is soluble in water and coagulable by heat, such as that found in egg white, milk, and (in particular) blood serum.

Transamination meaning - It is a chemical reaction that transfers an amino group to a ketoacid to form new amino acids.The product is usually alanine in the liver.

Deamination meaning - It is the removal of an amine group from a molecule of amino acid to produce ammonia (NH₃).

Detoxification of ammonia meaning - Ammonia is converted to a water soluble compound called urea.

Question 4

REVISE from SEM1 synthesis and transport and metabolism of lipids and fats.

Answer 4

Question 5

Describe the synthesis and excretion of cholesterol in the body.

Answer 5

• SYNTHESIS: -
  
  • 50% of cholesterol made in the body is made by the liver and the rest is made by the intestine, adrenal cortex and reproductive tissue.
  • It’s made from Acetyl CoA, and the key enzyme is HMG-CoA reductase.
  • It’s transported from the liver as VLDL (very low density lipoprotein).
• EXCRETION: -
  
  • The body cannot degrade cholesterol.
  • It is disposed of by the biliary system, either as unmodified cholesterol in bile or by following the conversion to bile acids/salts and secreted into the intestines.

Question 6

What are the two routes to the metabolism of ethanol (alcohol)?

Answer 6

1. Oxidation through the activity of alcohol dehydrogenase
   
   • ​​(90% of the alcohol we ingest is metabolised through this way).
2. Microsomal oxidation using cytochrome P450
   
   • (10-20% of the alcohol we ingest is metabolised through this way, but this changes when the consumption of alcohol increases).

Question 7

Describe the metabolism of ethanol (alcohol).

Answer 7

1. In the cytoplasm, ethanol is converted to acetaldehyde by alcohol dehydrogenase (it is a cytosolic enzyme) [NAD+ to NADH, H+].
2. Then, in the mitochondria, acetaldehyde is converted to acetate by aldehyde dehydrogenase (mitochondrial enzyme) [NAD+, H₂O to NADH, 2H+].
3. The acetate is then converted to acetyl CoA by the enzyme acetyl CoA synthase.

• Ethanol actually contains 7.1 kcal/g so it is a good energy source. But if you are an alcoholic it contains very little vitamin and mineral so it replresents ‘empty calories’. Hence alcoholics are prone to vitamin and mineral deficiencies as they can survive on the calories alone.
• The body has the capacity to metabolise 10g of alcohol/hour.
• The body can aso metabolise other alcohols such as methanol. However methanol is metabolised to form formaldehyde, which this is very toxic and is associated with paralysis, loss of consciousness and blindness.

Question 8

What is the cause of oriental flush and why is it limited to a certain ethnic group?

Answer 8

• Caucasians have two isoforms of the enzyme aldehyde dehydrogenase (1 and 2). The majority of the alcohol in these individuals will be metabolised by the second isoform (aldehyde dehydrogenase 2) which is a mitochondrial enzyme with a low Km (so a high affinity).
• Some ethnic groups have a reduced capacity (so their aldehyde dehydrogenase 2 enzyme is either absent or is present in a form that is not active). This prevents the metabolism of acetaldehyde. These individuals tend to have a low tolerance to alcohol. At one level it can lead to facial flush and the other level it can lead to nausea.

Question 9

List some pathways inhibited by the metabolism of ethanol.

Answer 9

1. Acetyl-CoA, NADH and ATP are formed to inhibit glucose metabolism by inhibiting phosphofructokinase (PFK) and pyruvate dehydrogenase.
2. NADH inhibits the TCA cycle (Krebs cycle) and this increases Acetyl-CoA further.
3. Acetyl-CoA results in ketone body formation (has an effect on circulating pH causing ketoacidosis) and the stimulation of fatty acid synthesis.
   
   • Fatty acids are esterified to triglycerides for export as VLDL and released into the blood causing hyperlipidaemia.
4. The high NADH/NAD ration pushes the activity of lactate dehydrogenase towards lactate resulting in lactic acidosis.
5. The high NADH/NAD ration inhibits gluconeogenesis in a fasting individual this would lead to hypoglycaemia.

Question 10

What is the microsomal ethanol-oxidising system (MESO)?

Answer 10

• This is the second route of metabolism.
• It involves oxidation by the members of the cytochrome P450 family of enzymes.
• This system uses NADPH which is required for the synthesis of the antioxidant glutathione.
  
  • (Glutathione protects the body from oxidative stress. So an increased alcohol consumption will lead a situation where the body is less able to protect itself from oxidative stress).

Question 11

Describe acetaldehyde.

Answer 11

• It is highly reactive and can accumulate with excessive ethanol intake.
• Because it is highly reactive, it can inhibit enzymes and their functions.
• In the liver, this can lead to a reduction in the secretion of both serum protein (they are important in blood clotting) and VLDL.
• It can also enhance free-radical production - leading to tissue damage such as inflammation and necrosis.

Question 12

What are the three stages of alcohol liver damage?

Answer 12

1. STAGE 1:
   
   • Fatty liver (deposition of excess fat within the tissue of the liver).
2. STAGE 2:
   
   • Alcoholic hepatitis, groups of cells die resulting in inflammation.
3. STAGE 3:
   
   • Cirrhosis which includes fibrosis, scarring and cell death.
   • As the cirrhotic liver cannot function properly, ammonia will accumulate (as the liver can no longer detoxify the ammonia produced from the breakdown of protein) resulting in neurotoxicity, coma and death.
   • Cirrhosis arises in 25% of alcoholics and 75% of all cirrhosis is due to alcohol.

Question 13

What are xenobiotics?

Answer 13

• They are compounds with no nutritional value (so the nody cannot deal with them as a food source) such as: -
  
  • Plant metabolites.
  • Synthetic compounds.
  • Food additives.
  • Agrochemicals.
  • Cosmetics.
  • By-products of cooking, etc.
  • Drugs.

Question 14

What does the liver have to do with xenobiotic metabolism?

Answer 14

• The liver plays a major role in xenobiotic metabolism (however it is not the only organ responsibke for this process).
• The aim is to make xenobiotics harmless and more readily disposed of by the kidney in the urine or the gut in the faeces.
• The intestine and the lungs are also involved.

Question 15

What are the three stages of the metabolism of xenobiotics?

Answer 15

There are three common phases: -

1. PHASE 1: Oxidation.
2. PHASE 2: Conjugation.
3. PHASE 3: Elimination.

This is the general pattern. There will be exceptions.

Question 16

Describe the first stage (oxidation) of xenobiotic metabolism.

Answer 16

• Oxidation is the most common modification, but we also get hydroxylation and reduction.
• This modification has the aim to increase solubility of the molecule.
• It introduces functional groups, which enables the molecule to participation in further reactions to aid its ultimate elimination.
• These reactions are promoted by a family of enzymes called cytochrome P450.

Question 17

Describe cytochrome P450.

Answer 17

• They are found mainly in the liver and cells of the intestine.
• They make up a family of about 50 different enzymes; they are all haem proteins (so they contain iron) and are related to the mitochondrial enzymes.
• They are found in the endoplasmic reticulum.
• An example of their action would be the hydroxylation of ibuprofen.
• P450 enzymes are inducible by both their substrates (5-10 fold), but also by related substrates (2-4 fold) [this is clinically important].

Question 18

Describe the second stage (conjugation) of xenobiotic metabolism.

Answer 18

• Xenobiotics are modified by the addition of groups such as:
  
  • Glutathione.
  • Glucuronic acid.
  • Sulphate
• Modification with these groups increases their solubility and targets them for excretion.
• The compounds are sequentially modified (there are multiple processes).

Question 19

Why is drug metabolism important? (useful drugs)

Answer 19

• Xenobiotics metabolism is part of the bodies natural defences.
• However the body does not distinguish between harmful compounds and beneficial compounds such as therapeutic drugs (hence some drugs are not delivered by ingestion because they will be metabolised quickly by the liver).
• Metabolism of drugs by the liver can play a significant role in their effectiveness.
• A drug taken orally will pass through liver first.
• Modifications made by the liver can significantly reduce the effectiveness of a drug.
• Although this could also be advantageous (It could activate a prodrug).

Prodrug meaning - It is a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug.

Question 20

Use statins as an example to describe how metabolism will effect the activity of the drug.

Answer 20

• Statins inhibit HMG-CoA reductase (so they are involved in regulating cholesterol metabolism).
• They are degraded by a cytochrome P450 enzyme (CYP3A4).
• This particular cytochromes (CYP3A4) activity is inhibited by components that are found in grapefruit juice.
• So if you take statins and also consume grapefruit juice in sufficient quantities this will have a significant effect on the circulating levels of that cholesterol as it will not be metabolised in the same way it would normally.

Question 21

Describe aflatoxin B1.

Answer 21

• It is produced by the fungues Aspergillus flavus.
• Aflatoxin is activated by P450 isoenzymes, which leads to epoxide formation (very toxic) and hepatocarcinogenesis.

Aflatoxin B1 is a member of a group of mycotoxins produced by Aspergillus flavus and A. parasiticus. AlflatoxinB1 is the most hepatotoxic and hepatocarcinogenic of the aflatoxins and occurs as a contaminant in a variety of foods.

Mycotoxins meaning - They are toxic compounds that are naturally produced by certain types of moulds (fungi).

Question 22

What happens to the modified compounds?

Answer 22

• The small, water-soluble molecules (of <60,000 kDa) can be removed by the kidney.
• They are activey transported in the bile and then into the intestines.
• The fate of these molecules are 3-fold:
  
  • Digestion.
  • Excretion.
  • Reabsorption (via the enterohepatic circulation).
• The fraction that is present in the circulation will decrease at each time the molecule is circulated (t_½ is the time required for 50% of a substance to be lost).
• This can effect low long you wait before you readminister a particular drug.