Metabolic Functions of the Liver Flashcards
What does the liver have to do with the digestive system?
The liver:
Receives blood from the gastrointestinal tract via the portal vein
This vein delivers major dietary nutrients; protein, carbohydrates but not lipids, (lipids are transported in the lymphatic system initially)
Also delivers drugs and potential toxins
Empties directly into major vessel entering the heart
Ensure rapid circulation of its products
Bile ducts empty directly into gut
Can rapidly influence the digestive process
What are the two routes to the metabolism of ethanol?
Oxidation through the activity of alcohol dehydrogenase- 90%
Microsomal oxidation using cytochrome P450- 10-20%
How is ethanol metabolised?
Ethanol is metabolised to Acetaldehyde (NAD+ to NADH, H) by alcohol dehydrogenase
Body metabolises approximately 10g of alcohol/hour
Methanol is metabolised to formaldehyde- this is very toxic and associated with blindness, paralysis and loss of consciousness
Ethanol contain 7.1 kcal/g if consumed as spirits it represents ‘empty calories’
How is Acetaldehyde metabolised?
Acetaldehyde is metabolised Acetate (NAD+ + H2O to NADH, 2H+)
Aldehyde dehydrogenase
Caucasians have two isoforms of the enzyme, ALDH-1 and 2, ALDH 2 is mitochondrial with a low km (so high affinity?)
40% of certain ethnic groups including Chinese, Japanese, Indonesians and Native Americans only express the less effective ALDH-1 which leads to ethanol intolerance
Suffer from with symptoms of vasodilatation, facial flush, tachycardia and nausea
What is the microsomal ethanol-oxidising system MESO?
MESO is the second route of ethanol metabolism
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
What is acetaldehyde like?
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
Can also enhance free-radical production- leading to tissue damage such as inflammation and necrosis
What are the three stages of liver damage?
Three stages of alcohol liver damage
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
What are the consequences of high ethanol metabolism?
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
What are xenobiotics?
Comes from the Greek meaning strange They are compounds with no nutritional value such as: Plant metabolites Synthetic compounds Food additives Agrochemicals Cosmetics By products of cooking Drugs
How does the liver play a major role in xenobiotic metabolism?
The aim to make xenobiotic harmless and more readily disposed of by the kidney in urine or the gut in faeces
Also involved are the intestines and the lungs
What are the stages of metabolism of xenobiotics?
Three common phases:
Phase I- Oxidation
Phase II- Conjugation
Phase III- Elimination
What is the oxidation phase of xenobiotic metabolism?
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 pf enzymes called cytochrome P450
What is the conjugation phase of xenobiotic metabolism?
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
Why is the liver and drug metabolism?
Xenobiotics metabolism is part of the bodies natural defences
However the body does no 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
Although this could also be advantageous
What is Aflatoxin B1?
Produced by the fungus Aspergillus flavus
Aflatoxin activated by P450 isoenzymes leading to epoxide formation and hepato-carcinogenesis
