Metabolic Functions of the Liver

Question 1

What’s the liver’s role in digestion?

What’s the liver’s role with cholesterol and bile salts?

Answer 1

• • Handles large amounts of newly absorbed nutrients before it goes into the IVC - portal system
  • Produces and empties bile into duodenum
• • 50% of Cholesterol is made in liver from Acetyl CoA - transported out as VLDL
  • Excretion of cholesterol in bile or as bile acids

Question 2

Describe the steps in Ethanol Metabolism

What are the consequences of Ethanol metabolism?

LOOK AT DIAGRAM!

Answer 2

• • Oxidation through Alcohol Dehydrogenase or Microbial oxidation through Cytochrome P450
  • Ethanol is metabolised to Acetaldehyde and then to Acetate - Acetaldehyde dehydrogenase in mitochondria has a low Km
• Oxidation of alcohol isn’t regulated by negative feedback. As a result, lots of Acetyl-CoA, NADH, and ATP is made, which inhibits:
  Glucose Metabolism - inhibits PFK and Pyruvate Dehydrogenase
  • TCA cycle - due to depletion of NAD
  • Lipolysis - through stimulation of Lipogenesis
• Acetaldehyde produced is highly reactive - inhibits enzyme function, reduces liver protein and VLDL secretion, and enhances free-radical production
• Liver damage starts with Fatty liver → Alcoholic Hepatitis → Cirrhosis - can’t perform normal functions

Question 3

What are Xenobiotics?

What does the liver do the xenobiotics?

What is the Cytochrome P450 family?

Answer 3

• • Compounds with no nutritional value e.g. plant metabolites, food additive, DRUGS
  • Water soluble compounds excreted easily in the urine
• Makes them harmless and ↑Ease of excretion
• • 50 different Haem proteins found in the Endoplasmic reticulum
  • Related to mitochondrial enzymes
  • Inducible by their own substrates and other related substances

Question 4

What are the 3 phases of Xenobiotic (Drug) metabolism?

Answer 4

Phase I: Oxidation
• Most common modification, along with hydroxylation and reduction = ↑Solubility
• Introduces functional groups to allow for further reactions
• Reactions promoted by Cytochrome P450 family

Phase II: Conjugation
• Addition of groups e.g. Glutathione, Glucuronic acid, Sulphate - this ↑Solubility and targets them for excretion

Phase III: Elimination
• Small water-soluble molecules can be removed by the kidney
• Active transport into bile and then into bowel
• The outcomes of the molecules - Digestion, Excretion, Re-absorption

Question 5

What’s the importance of Xenobiotic metabolism?

Give 2 examples of Xenobiotic metabolism

Answer 5

• • Part of body’s natural defences - however, metabolism of drugs by the liver can play a role in their effectiveness
  • Oral drugs will pass through the liver first, so modifications to it can significantly reduce the drug’s effectiveness - but it could also be advantageous
• • Statins - degraded by Cytochrome P3A4, which can be inhibited by grapefruit juice to elevate statin levels.
  • Aflatoxin B1 - activated by Cytochrome P450 to form epoxide (carcinogen) - harmful