Metabolic Functions of the Liver

Question 1

State the metabolic processes the liver plays a central role in

Answer 1

• Regulation of carbohydrate metabolism - to maintain blood glucose
• Regulation of fat metabolism - synthesis and beta oxidation
• Regulation of protein metabolism - plasma protein synthesis, detoxification of ammonia - urea formation
• Cholesterol synthesis and excretion
• Synthesis of specialised molecules - bile acids and haemin

Question 2

Where does the liver receive blood from and what is in this blood?

Answer 2

• From the GI tract via the portal vein
• Delivers major dietary nutrients - proteins, carbohydrates but not lipids
• Also delivers drugs and potential toxins

Question 3

State the 2 main pathways for the metabolism of ethanol

Answer 3

There are two routes to the metabolism of ethanol:
- Oxidation through the activity of alcohol dehydrogenase (90%)
- Microsomal oxidation using cytochrome P450 (10-20%)

Question 4

How much ethanol can the body metabolise?

Answer 4

10g of alcohol an hour per route 1

Question 5

What does methanol form when metabolised?

Answer 5

Methanol is metabolised to form formaldehyde which is very toxic and associated with blindness, paralysis and loss of consciousness

Question 6

Describe ethnic differences in ethanol metabolism

Answer 6

• Caucasians have 2 isoforms of the aldehyde dehydrogenase enzyme ALDH-1 and 2,ALDH 2 is mitochondrial with a low Km
• 40% of certain ethnic groups e.g. Chinese, Japanese, Indonesians and Native Americans only express the less effective ALDH 1 so have ethanol intolerance

Question 7

Describe route 1 and route 2 of ethanol metabolism

Answer 7

Route 1-
1. Ethanol is dehydrogenated via NAD+ to form NADH to form acetaldehyde via cytosolic alcohol dehydrogenase
2. Acetaldehyde is then converted to acetate via mitochondrial aldehyde dehydrogenase by reacting with NAD+ and H2O to also form NADH and 2H+
3. Acetate is then converted to acetyl coA by acetyl coA synthase

Route 2 -
- Involves the oxidation of ethanol by members of the cytochrome P450 family of enzymes
- The pathway generates acetaldehyde
- As the system consumed NADPH needed for the synthesis of the antioxidant glutathione it results in increased oxidative stress

Question 8

Why can large amounts of acetyl coA, NADH and ATP form in ethanol metabolism?

Answer 8

Metabolism of ethanol is not regulated by negative feedback

Question 9

Describe acetaldehyde including its properties and the effects it can have

Answer 9

• Highly reactive and can accumulate with excessive ethanol intake
• Acetaldehyde is very reactive and can inhibit enzyme function
• In the liver this can lead to a reduction in the secretion of both serum proteins and VLDL
• Can also enhance free radical production - leading to tissue damage such as inflammation and necrosis

Question 10

State the 3 stages of liver damage and what occurs after these stages

Answer 10

3 stages of alcohol liver damage:

• Stage 1 - fatty liver
• Stage 2 - alcoholic hepatitis - groups of cells die causing inflammation
• Stage 3 - cirrhosis which included fibrosis scarring and cell death
• As the cirrhotic liver cannot function properly ammonia will accumulate resting in neurotoxicity coma and death

Question 11

Describe the consequences of high ethanol metabolism

Answer 11

• High NADH inhibits gluconeogenesis and stimulates the conversion of pyruvate to lactate leading to hypoglycaemia and lactic acidosis
• High NADH inhibits fatty acid oxidation and stimulates fatty acid synthesis and the formation of triglycerides
• Acetyl coA , NADH and ATP formed inhibit glucose metabolism by inhibiting phosphofructokinase and pyruvate dehydrogenase
• NADH inhibits the TCA cycle and acetyl coA increases the inhibition further
• Acetyl coA results in ketone body formation and the stimulation of fatty acid synthesis

Question 12

Describe what xenobiotic compounds are and some examples

Answer 12

These are compounds with no nutritional value such as: plant metabolites, synthetic compounds, food additives, agrochemicals, cosmetics, by products of cooking, drugs

Question 13

What does the liver aim to do to xenobiotic compounds?

Answer 13

The aim of the liver is to make xenobiotics harmless and more readily disposed of by the kidney in the urine or the gut in the faeces

Question 14

State the 3 common phases of xenobiotic metabolism

Answer 14

Phase 1 oxidation
Phase 2 conjugation
Phase 3 elimination

Question 15

State the other processes that can happen instead of oxidation

Answer 15

Oxidation is the most common modification but can also be hydroxylation and reduction

Question 16

What is the function of oxidation?

Answer 16

• This modification increases solubility
• Introduces functional groups that enable participation in further reactions
• These reactions are promoted by a family of enzymes called cytochrome P450

Question 17

Describe cytochrome P50 enzymes

Answer 17

• Found mainly in the liver and cells in the intestine
• Make up a family of about 50 different enzymes they are haem proteins 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 both by their own substrates but also related substrates
• This has clinical importance

Question 18

Describe what happens during phase 2 conjugation

Answer 18

• Modified by addition of groups such as glutathione, glucuronic acid, sulphate
• Modification with these groups increase solubility and targets them for excretion

Question 19

Describe the significance of xenobiotic metabolism in terms of drug compounds

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
• Metabolism of drugs by the liver can play a significant role in their effectiveness - a drug taken orally will pass through the liver first - modifications made by the liver can significantly reduce the effectiveness of a drug although this could also be advantageous

Question 20

State two examples where the P450 system does not have the expected effect

Answer 20

Aflatoxin B1 -
- Produced by the fungus aspergillus flavus
- Aflatoxin activated by P450 isoenzymes leading to epoxide formation and hepatocarcinogenesis

Statins -
- Statins inhibit HMG coA reductase and are degraded by CYP3A4
- CYP3A4 activity is inhibited by grapefruit juice
- Statin levels can rise by 15 fold

Question 21

Describe the metabolism of paracetemol under normal conditions

Answer 21

• Under normal conditions the goal is to form soluble compounds that can be easily excreted
• The first reaction is conjugation via UDP glucuronyl transferase to form glucoronate which is readily exceeted via the kidney in the urine
• Or the paracetemol is sulphated via sulpho transferase to form a soluble compound excreted via the kidney in the urine
• A proportion of the paracetemol will also be converted into NAPQI which is a very toxic intermediate product
• To stop it having toxic effects it is usually conjugated with glutathione (glutathione s transferase) to form mercapturic acid which can be excreted via the kidney in the urine

Question 22

Describe what happens to paracetemol metabolism under high ethanol influence

Answer 22

• If the conjugation of the toxic intermediate with glutathione is prevented then:
• The toxic intermediate can also react with a cell protein to form a NAPQI protein adduct which causes tissue damage and death
• Ethanol stimulates the enzyme cytochrome P2E1 which causes increased formation of the toxic product
• Because NADPH is needed in ethanol metabolism there is less available to form glutathione so less of the toxic product is able to conjugate with it to form a harmless water soluble product and so more tissue damage/death occurs

Question 23

What happens to the modified components after liver metabolism?

Answer 23

• Small water soluble molecules less than 60,000 kDa can be removed by the kidney
• Actively transported into the bile then the intestines
• The fate of these molecules are 3 fold - digestion, excretion, reabsorption via the enterohepatic circulation