Metabolism S6 - Alcohol Metabolism Flashcards
Where is the major site of alcohol metabolism?
The Liver
Outline alcohol metabolism
- alcohol dehydrogenase oxidises alcohol to acetaldehyde
- Acetaldehyde is further oxidised to acetate by aldehyde dehydrogenase
- The acetate is then converted into acetyl CoA and enters general metabolism
- Smaller amounts can also be oxidised by the inducible enzyme cytochrome P450 2E1. or by catalase in the brain
Why and how is acetaldehyde levels kept to a minimum?
Acetaldehyde is extremely toxic to a cell
Toxicity is kept to a minimum as aldehyde dehydrogenase has a very low Km for it
Why does prolonged alcohol consumption have an effect of liver metabolism?
- Acetaldehyde accumulation
- Decrease in the NAD+:NADH ratio
- Increased availability of acetyl CoA
What effect does the decreased NAD+ : NADH ratio have on liver metabolism? (Alcohol metabolism)
- Increased levels of NADH in the liver caused by alcohol oxidation means that NAD+ levels are inadequate for fatty acid oxidation, conversion of lactate to pyruvate and metabolism of glycerol
- The decreased utilisation of lactate leads to its accumulation and may cause lactic acidosis
- Increased levels of lactate reduce the kidney’s ability to excrete uric acid; as uric acid levels increase, crystals of urate accumulate causing gout
- The low NAD+ level combined with inability of liver cells to use lactate or glycerol means that gluconeogenesis cannot be activated and fasting hypoglycaemia may become a serious problem
What effect does increased availability of acetyl CoA? (Alcohol metabolism)
- Increased acetyl CoA in liver cells at a time when it cannot be oxidised due to the low NAD+ : NADH ratio, leads to increased synthesis of fatty acids and ketone bodies
- The fatty acids are converted into TAGs
- TAGs cannot be transported from the liver due to lack of lipoprotein synthesis and therefore contributes to fatty liver
- In some cases, the production of ketone bodies causes keto-acidosis
What effect does alcohol have on the gastrointestinal tract?
- High levels of alcohol damage the cells lining the GI tract and produce a variety of GI tract disturbances
- Loss of appetite
- Diarrhoea
- Impaired absorption
How can chronic heavy alcohol consumption possibly lead to diabetes?
- Chronic heavy alcohol consumption can lead to chronic inflammation of the pancreas (chronic pancreatitis)
- Damage to the pancreas from alcohol abuse may not cause any symptoms for several years before severe pancreatitis forms
- The damage could lead to loss of insulin producing β-cells
What is used to treat alcohol dependence?
Disulfiram
How does disulfiram work?
- Inhibits aldehyde dehydrogenase enzyme
- If patients drink alcohol, acetaldehyde accumulates in the blood causing the symptoms of a hangover such as nausea
- With additional support, an effective way to treat alcohol dependence
Outline paracetamol metabolism
Under normal conditions
- Metabolised in the liver by conjugation with glucuronide or sulphate yielding relatively non-toxic metabolites
Overdose ~10g
- Paracetamol metabolism produces the metabolite NAPQI
- NAPQI is incredibly toxic to hepatocytes
- NAPQI is a strong oxidising agent and undergoes conjugation with glutathione, thereby depleting important this important anti-oxidant
- The direct oxidative toxic effects of NAPQI causing covalent binding in hepatic proteins together with the resulting oxidative stress from glutathione depletion results in the destruction of liver cells and liver failure occurs over a period of several days eventually causing death
What is used to treat paracetamol overdose?
Acetylcysteine
Replenishes glutathione allowing the liver to safely metabolise the NAPQI
