30) Metabolic Functions of the liver

Question 1

What are the roles of the liver?

Answer 1

• Regulation of carbohydrate metabolism and to maintain blood glucose level
• Regulation of fat metabolism through the regulation of synthesis and degradation/β-oxidation
• Regulation of protein metabolism through the synthesis of plasma proteins and detoxification of ammonia through urea formation
• Cholesterol synthesis and excretion
• Synthesis of specialised molecules such as bile acids and haemin

Question 2

How is the liver perfuesed?

Answer 2

• The portal vein delivers major dietary nutrients such as proteins and carbohydrates in the blood from the GI tract to the liver
• The portal vein also delivers drugs and toxins but it does not deliver lipids
• The lipids are transported in the lymphatic system to the heart, bypassing the liver
• The blood in the liver then empties into major vessles entering the hear (inferior vena cava) and is important as it directly supplies nutrients to the circulation

Question 3

Where is bile secreted?

Answer 3

• Bile ducts secrete bile directly into the gut which can rapidly influence the digestive process

Question 4

What are the mechanisms by which ethanol can be metabolised?

Answer 4

• Oxidation through the activity of the enzyme alcohol dehydrogenase (more commonly used)
• Microsomal oxidation using cytochrome P450 (less commonly used)

Question 5

How does oxidation through alcohol dehydrogenase occur?

Answer 5

• First ethanol is metabolised through alcohol dehydrogenase (which is a cytosolic enzyme) resulting in the formation of Acetaldehyde. This process requires NAD+
• Acetaldehyde is converted to acetate through the enzyme aldehyde dehydrogenase (which is a mitochondrial enzyme). This process uses NAD+ and H2O
• The acetate can then be converted to Acetyl CoA through Acetyl CoA synthase
• Acetyl CoA can be converted into energy or fatty acids

Question 6

How is methanol metabolised by alcohol dehydrogenase?

Answer 6

• Methanol can also be metabolised however it forms formaldehyde which is very toxic and associated with blindness, paralysis and loss of consciousness

Question 7

Why do some people suffer from ethanol intolerance?

Answer 7

• Caucasians have two isoforms of aldehyde dehydrogenase (ALDH): ALDH-1 and ALDH-2
• Most ethnic groups only express ALDH-1
• ALDH-1 has a higher Km than ALDH-2.
• This means that ALDH-1 is less effective and therefore leads to ethanol intolerance
• Symptoms of ethanol intolerance includes vasodilation, facial flush, tachycardia and nausea

Question 8

How does Microsomal Ethanol-Oxidising System (MESO) occur?

Answer 8

• It invovles the oxidation of ethanol by members of cytochrome P450 .
• This pathway generates acetaldehyde
• This system consumes NADPH which is required for the synthesis of the antioxidant glutathione that results from increased oxidative stress

Question 9

What is acetaldehyde?

Answer 9

• A highly reactive molecule which can accumulate with excess ethanol intake
• It can inhibit enzyme function and so causes a reduction in the synthesis of serum proteins and VLDLs leading to the further accumulation of fats in the liver
• It can enhance free-radical production leading to tissue damage such as inflammation and necrosis

Question 10

What are the three stages of liver damage?

Answer 10

• Stage 1: Fatty liver
• Stage 2: Alcoholic hepatitis where groups of cells die as a result of inflammation
• Stage 3: Cirrhosis which includes fibrosis, scarring and cell death
• When cirrhosis occurs the liver is unable to function properly so ammonia builds up (due to a decreased production of urea) and will accumulate leading to neurotoxicity, coma and death

Question 11

What are the consequences of high ethanol metabolism?

Answer 11

• High NADH (caused by alcohol dehydrogenase system) inhibits gluconeogenesis and stimulates the conversion of pyruvate to lactate which leads to hypoglycaemia and lactic acidosis
• High NADH levels also inhibits fatty acid oxidation while also stimulating fatty acid synthesis and the formation of triglycerides. This causes a fatty liver (Stage 1) to form
• Acetyl-CoA, NAD and ATP formed inhibit glucose metabolism by inhibiting Phosphofructokinase and pyruvate dehydrogenase.
• NADH inhibits the TCA cycle and causes Acetyl-CoA accumulation which increases inhibition futher
• Acetyl-CoA accumulation can also result in ketone body formation and the stimulation of fatty acid synthesis

Question 12

What are xenobiotics?

Answer 12

• Compounds that have no nutritional value (e.g. synthetic compounds, cosmetics, drugs, etc)
• The liver plays a role in the metabolism of xenobiotics
• It aims to make these xenobiotics harmless and make them more readily disposed off by the kidneys (through urine) or by the gut (through faeces)
• The intestines and lungs are also involved in this process

Question 13

What are the common phases of the metabolism of xenobiotics?

Answer 13

• Phase 1: Oxidation
• Phase 2: Conjugation
• Phase 3: Elimination

Question 14

What is oxidation of xenobiotics?

Answer 14

• Oxidation of xenobiotics is the most common modification however other modifications such as hydroxylation and reduction can occur
• They introduce functional groups that can increase solubility or helps them take part in further reactions
• These reactions are promoted by the family of Cytochrome P450 enzyme

Question 15

What is cytochrome P450 enzymes?

Answer 15

• Found mainly in the liver and intestinal cells
• They are haem proteins
• They are found in the ER and are inducible/activated by their own substrates (to produce a large effect) or by related substrates (producing a smaller effect)

Question 16

What is conjugation of xenobiotics?

Answer 16

• Xenobiotics are modified by addition of other groups such as glutathione, glucuronic acid and sulphate
• Modification of these groups increases solubility and targets them for excretion
• These compounds are modified in a sequential manner

Question 17

Why is drug metabolism by the liver important?

Answer 17

• Xenobiotic metabolism is part of the body’s natural defence
• 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

Question 18

Why is drug metabolism by the liver taken into account when designing a new drug?

Answer 18

• When a drug is taken orally the contents are pass through the liver via the portal vein
• Modifications made by the liver can significantly reduce the effectiveness of the drug
• Although this can be advantageous

Question 19

How is aflatoxin B1 affected by cytochrome P450?

Answer 19

• Produced by fungal contamination commonly found in peanuts
• The aflatoxin is activated by P450 isoenzyme leading to epoxide (which is very toxic) formation which stimulates hepato-carcinogenesis

Question 20

How are the levels of statin affected?

Answer 20

• Statins regulate cholesterol biosynthesis by inhibiting HMG-CoA reductase and under normal circumstances are degraded by cytochrome P3A4
• However cytochrome P3A4 activity can be inhibited by grapefruit juice and so can lead to a massive increase in statin level

Question 21

How is paracetamol metabolised normally?

Answer 21

• Under normal circumstances the paracetamol is metabolised into soluble compounds that are readily secreted by the kidneys
• A small proportion of the paracetamol will be converted to a toxic intermediate which will normally be conjugated to form a water soluble molecule which can be excreted
• If the conversion of this intermediate is inadequate, it will build up and will form a second product called a protein adduct.
• This protein adduct is toxic as they induce oxidative stress leading to tissue damage and death

Question 22

How does ethanol affect paracetamol metabolism?

Answer 22

• Ethanol increases the conversion of paracetamol to the toxic intermediate by stimulating the enzyme involved in the reaction
• Ethanol consumes NADPH which is required in the synthesis of the enzyme that conjugates the toxic intermediate into the soluble product.
• So by consuming NADPH more of the toxic intermediate is converted to the protein adduct
• Hence there is an increase in the toxic intermediate concentration and an increase in protein adduct concentration

Question 23

What happens to modified compounds?

Answer 23

• Small water soluble molecules can be removed by the kidneys
• They can also be transported into bile and then released into the small intestines via the bile duct. These molecules can either be digested, excreted, or reabsorbed
• As time goes on concentration of these compounds in the body will fall