Metabolic functions of the liver Flashcards
Explain how the liver plays a central role in metabolism of many nutrients
1) regulation of carbohydrate metabolism
-to maintain blood glucose
2) regulation of fat metabolism:
-synthesis
-B-oxidation
3) regulation of protein metabolism:
-plasma protein synthesis
-detoxification of ammonia (urea formation)
4) cholesterol synthesis and excretion
5) synthesis of specialised molecules:
-bile acids
-haemin
What are the functions of the liver
Functions of the liver:
1) receives blood from the gastrointestinal tract via the portal vein
2) delivers major dietary nutrients, protein, carbohydrates
3) delivers drugs and potential toxins
4) empties directly into major vessel entering the heart
5) ensure rapid circulation of its products
6) bile ducts empty directly into gut
7) can rapidly influence the digestive process
Explain why we ingest ethanol
we ingest ethanol as a consequence of both diet and life style
Explain two routes of metabolism for ethanol
there are two routes to the metabolism of ethanol:
1) oxidation through the activity of alcohol dehydrogenase (NADH+ involved)- 90% metabolism of ethanol
2) Microsomal oxidation using cytochrome P450 (10-20%) (MESO)
Explain the stages between metabolism of ethanol using alcohol dehydrogenase
1) Ethanol is converted to Acetaldehyde using NADH and H+
2) this uses the enzyme alcohol dehydrogenase
3) Acetaldehyde is converted to acetate by sing NADH and 2H+ by splitting H20 molecule via hydrolysis
4) this uses the enzyme aldehyde dehydrogenase
Describe methanol
methanol is metabolised to formaldehyde,
-this is very toxic and is associated with blindness, paralysis and loss of consciousness
Explain metabolism of acetate in detail
1) Acetate is converted to Acetyl CoA by acetyl CoA synthase
Explain different ethnic groups and the enzyme aldehyde dehydrogenase
-Caucasians have two isoforms of the enzyme (ALDH-1 and 2) ALDH-2 is mitochondrial with a low km
-40% of certain ethnic groups only (e.g. Chinese, Japanese, Indonesians and native Americans) only express the less effective ALDH-1 which leads to ethanol intolerance
-suffers from vasodilation, facial flush, tachycardia and nausea
explain microsomal ethanol-oxidising system (MESO)
- MESO is the second route of ethanol metabolism
-involve 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
Explain acetaldehyde
-is highly reactive and can accumulate with excessive ethanol intake
-acetylaldehyde is very reaction 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
Explain the three stages of alcohol liver damage
stage 1: fatty liver
Stage 2: alcoholic hepatitis (groups of cells die resulting in inflammation)- this can cause scarring
Stage 3: cirrhosis which includes fibrosis, scarring 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 consequences of high NADH
-High NADH inhibits gluconeogenesis (formation of glucose) and stimulates conversion of Pyruvate to lactate leading to hypoglycaemia and lactic acidosis.
-High NADH inhibits fatty acid oxidation + stimulates fatty acid synthesis and formation of triglycerides
What inhibits glucose metabolism
Acetyl CoA, NADH and ATP formed inhibit glucose metabolism by inhibiting PFK and Pyruvate dehydrogenase
What inhibits the TCA cycle
NADH inhibits the TCA cycle so less respiration and acetyl coA increases inhibition further
What results in ketone body formation
Acetyl CoA results in ketone body formation and the stimulation of fatty acid synthesis
Give a summary of ethanol metabolism
-oxidation of alcohol takes precedence over other nutrients (oxidation of alcohol firstly)
-metabolism of alcohol is not regulated by negative feedback
-as a result, large quantities of acetyl CoA, NADH and ATP are formed
What are xenobiotics and examples of them
They are compounds with no nutritional value such as:
-plant metabolites
-synthetic compounds
-food additives
-agrochemicals
-cosmetics
-by products of cooking
-drugs
Explain how the liver plays a major role in xenobiotic metabolism
-the aim of the liver is to make xenobiotics harmless and more readily disposed by the kidney in urine or the gut in fences
What are 3 common phases in the metabolism of xenobiotics
Three common phases:
1) Phase 1 oxidation
2) Phase 2 conjugation
3) Phase 3 elimination
Explain what happens in phase 1 oxidation
-oxidation is the most common modification but there is also hydroxylation and reduction
-modification increases solubility by forming more H bonds in water
-introduces functional groups which enables participation in further reactions
-these reactions are promoted by a family of enzymes called cytochrome P450
Explain characteristics of Cytochrome P450
-found mainly in the liver and cells of the intestine
-make up a family of 50 different enzymes ——> haem proteins and are related to mitochondrial enzymes
-they are found in the endoplasmic reticulum
-clinically important
Explain conjugation (phase 2)
Xenobiotics are modified by addition of groups such as:
-glutathione
-glucuronic acid
-sulphate
Modification with these groups increases solubility and targets them for excretion
Why is xenobiotics metabolism important
-xenobiotics metabolism is part of the bodies natural defences
-the body cannot distinguish between harmful and beneficial compounds
-metabolism of drugs by the liver can play a significant role in their effectiveness.
-modifications made by the liver can significantly reduce the effectiveness of the drug
Describe aflatoxin B1
-This is a fungal toxin produced by Aspergillus flavus
-Aflatoxin activated by P450 isoenzymes leading to epoxied formation and hepato-carcinogenesis
Explain statins
-statins inhibit HMG-CoA reductase
-are degraded by CYP3A4
-CYP3A4 activity is inhibited by grapefruit juice
Explain the metabolism of paracetamol through a safe pathway
Glucuronidation → forms a harmless product (Glucoronate)
Sulfation → also forms a harmless product (SO₄ version)
These are both eliminated via the kidneys (urine).
➡️ This is how most of the drug is handled.
Explain metabolism of paracetamol through the risky pathway
Some of the drug is processed by an enzyme called CYP2E1, producing a toxic intermediate called NAPQI.
Normally, NAPQI is neutralized by something called GSH (glutathione).
With GSH, NAPQI is safely turned into mercapturic acid and removed by the kidneys.
Explain the metabolism of paracetamol through an overdose of paracetamol or alcohol
If too much NAPQI is made or not enough GSH is available:
NAPQI binds to cell proteins, forming a toxic compound.
This leads to tissue damage, especially in the liver, and can cause death.
What happens to the modified compounds
-small water soluble molecules can be removed via kidneys
-actively transported into bile and then to the intestines
The fat of these molecules are:
-digestion
-excretion
-re-absorption via the enterohepatic circulation
