metabolic functions of the liver

Question 1

how does the liver play a role in the metabolism of nutrients ?

Answer 1

• Regulation of carbohydrate metabolism
  -To maintain blood glucose
• Regulation of fat metabolism
• synthesis
• degradation (β-oxidation)
• Regulation of protein metabolism
• Plasma protein synthesis
• Detoxification of ammonia - Urea formation
• Cholesterol synthesis and excretion
• Synthesis of specialized molecules
• bile acids
• haemin

Question 2

why does the liver play a central role ?

Answer 2

• due to the anatomical position
• receives blood from GI tract via portal vein - metabolise components that have been absorbed from the diet
• delivers major dietary nutrients protein, carbohydrates but not lipids
• also delivers drugs and potential toxins
• Empties directly into major vessel entering the heart.
• Ensures rapid circulation of its products.
• Bile ducts empty directly into gut.
• Can rapidly influence the digestive process

Question 3

what are the 2 routes of metabolism of ethanol ?

Answer 3

• Oxidation through the activity of alcohol dehydrogenase
  90%
• Microsomal oxidation using cytochrome P450
  10-20%

Question 4

describe the most common route of ethanol metabolism

Answer 4

1. ethanol converted to acetaldehyde via the enzyme Alcohol dehydrogenase using NAD and converting it to NADH. this is a cytosolic process and also the rate determining step.
   * methanol is converted to formaldehyde - very toxic and associated with blindness and paralysis.
2. acetaldehyde converted to acetate via aldehyde dehydrogenase. uses NAD and water. this is a mitochondrial process.
3. acetate can be converted to acetylCoA
   * if in liver acetylCoA can be converted to fats.
   * in non hepactic tissue acetylCoA can be used in TCA cycle to produce energy.

Question 5

why are ethnic groups such as Japanese or Chinese more likely to suffer symptoms such as vasodilation , facial flushes , tachycardia and nausea when drinking alcohol ?

Answer 5

• aldehyde dehydrogenase has 2 isoforms
• ALDH 1 & 2
• 40% of certain ethnic groups including Chinese, Japanese, Indonesians and Native Americans only express the less effective ALDH -1 which leads to ethanol intolerance

Question 6

describe the less common route of ethanol metabolism

Answer 6

• microsomal ethanol oxidising system - MESO
• Involves the oxidation of ethanol by members of the cytochrome P450 family of enzymes.
• The pathway generates acetaldehyde
• As this system consumes NADPH required for the synthesis of the antioxidant glutathione it results in increased oxidative stress

Question 7

what can occur due to an accumulation of acetaldehyde ?

Answer 7

• Is 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 protein and VLDL ( inhibition of VLDL secretion can lead to build up of fats within the liver)
• Can also enhance free-radical production – leading to tissue damage such as inflammation and necrosis

Question 8

what are the 3 stages of alcohol liver damage ?

Answer 8

• Stage 1: Fatty liver
• Stage 2: alcoholic hepatitis, groups of cells die resulting in inflammation
• Stage 3: Cirrhosis which includes fibrosis, scaring and cell death
• As the cirrhotic liver cannot function properly ammonia will accumulate resulting in neurotoxicity, coma and death
• Cirrhosis arises in 25% of alcoholics and 75% all cirrhosis is due to alcohol

Question 9

what are the consequences of high ethanol metabolism ?

Answer 9

• 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 PFK 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 10

what are xenobiotics ?

Answer 10

compounds with no nutritional value
eg:
plant metabolites
synthetic compounds
food additives
agrochemicals
cosmetics
by-products of cooking
drugs

Question 11

how does the liver play a major role in xenobiotic metabolism ?

Answer 11

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

Question 12

what are the 3 common stages of xenobiotic metabolism ?

Answer 12

Phase I oxidation
Phase II conjugation
Phase III elimination

Question 13

describe phase 1 - oxidation

Answer 13

• Oxidation is the most common modification but also get hydroxylation and reduction
• Modification increases solubility
• Introduces functional groups which enables participation in further reactions
• These reactions are promoted by a family of enzymes called cytochrome P450

Question 14

what are cytochrome P450s ?

Answer 14

• Found mainly in liver and cells of 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 (5-10 fold) but also related substrates (2-4 fold)

Question 15

describe phase 2 - conjugation

Answer 15

• Xenobiotic are modified by addition of groups such as:
  Glutathione
  Glucuronic acid
  Sulphate
• Modification with these groups increase solubility and targets them for excretion
• Compounds are often sequentially modified

Question 16

why is xenobiotic metabolism important ?

Answer 16

• 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 liver first
• Modifications made by the liver can significantly reduce the effectiveness of a drug

Question 17

what is aflatoxin B1 ?

Answer 17

• common on peanuts
• Produced by the fungus Aspergillus flavus
• Aflatoxin activated by P450 isoenzymes leading to epoxide formation and hepato-carcinogenesis
• P450 system works against us

Question 18

what do statins do ?

Answer 18

• Statins inhibit HMG-CoA reductase
• Are degraded by CYP3A4
• CYP3A4 activity inhibited by grapefruit juice
• statin levels can rise by 15 fold

Question 19

describe the metabolism of paracetamol

Answer 19

• Most of the paracetamol is conjugated with either glucoronate or sulphate and excreted by the kidney.
• Approximately 10% of the hepatic metabolism of paracetamol results in the production of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI).
• Under physiological conditions NAPQI is cleared by its conjugation with glutathione (GSH).
• If it is not cleared then the NAPQI will form NAPQI-protein adducts resulting in oxidative stress, mitochondrial dysfunction, and necrotic cell death.
• The problem arises when the levels of GSH are insufficient.
• NADPH is required for the synthesis of GSH. So in summary ethanol metabolism leads to a reduction in NADPH a reduction in GSH required to clear NAPQI. NADQI builds up causing liver damage.

Question 20

what happens to the modified compounds ?

Answer 20

• Small water soluble molecules <60,000kDa can be removed by the kidney
• Actively transported in to bile and then into the intestines
• The fate of these molecules are 3 fold
• Digestion
• Excretion
• Re-absorption via the enterohepatic circulation
• t½ is the time required for 50% of a substance to be lost