Alcohol metabolism & Oxidative stress Flashcards
Describe the metabolism of alcohol and explain how the metabolism can cause damage to the liver.
Most (90%) of the alcohol is metabolised. Most of the alcohol is oxidised by alcohol dehydrogenase to acetaldehyde and this is further oxidised to acetate by aldehyde dehydrogenase. The acetate is then converted to acetyl CoA and enters general metabolism. This can be harmful to the liver as acetaldehyde is toxic to cells. Prolonged alcohol consumption can cause sufficient acetaldehyde accumulation which causes liver damage. Excess NADH and acetyl CoA leads to changes in liver metabolism
-fatty liver
-Alcohol hepatitis
-Alcohol cirrhosis
Explain the mechanism of action of Disulfiram in the treatment of alcohol dependence
Disulfiram is a drug which can be used as an adjunct in the treatment of chronic alcohol dependence. It is an inhibitor of the enzyme aldehyde dehydrogenase. If the patient drinks alcohol, then acetaldehyde will accumulate in the blood causing symptoms of a ‘hangover’ such as nausea. With additional support, it can be effective in treating alcohol dependence.
Describe the production of superoxide radicals by mitochondria and discuss other reactive oxygen (ROS) and reactive nitrogen (RNS) species
In the electron transport chain, in mitochondria, the final destination for an electron is usually an oxygen molecule which is then combined with protons to produce water. However, about 0.1-2% of electrons do not reach the end of the chain and they prematurely reduce oxygen to form superoxide. Superoxide with its unpaired electron, is a highly reactive free radical which together with hydrogen peroxide and hydroxyl radicals constitute a group of species known as reaction oxygen species.
ROS - Superoxide, hydrogen peroxide, hydroxyl radical
RNS - nitric oxide
Outline the cellular defences against reactive oxygen species and explain the roles of oxidative stress in disease states.
There are several protective defence mechanisms as there is a big range of damage that ROS can cause. This includes:
-Superoxide dismutase/catalase - SOD counters the damaging effects of superoxide by catalysing its conversion to hydrogen peroxide and oxygen. Hydrogen Peroxide is a powerful oxidising agent and is rapidly broken down to molecular oxygen and water by the enzyme catalase.
-Glutathione - GSH is a tripeptide with a gamma peptide linkage between the carbonyl group of the glutamate sidechain and the amine group of cysteine. Glutathione is synthesised by the body as an antioxidant to protect against oxidative damage. The thione group of the Cys residue donates an electron to ROS and reacts with another GSH forming a disulphide bond (GSSG)
GSH to GSSG catalysed by glutathione peroxidase (requires trace element selenium)
GSSG to GSH reduced by glutathione reductase which catalyses the transfer of electrons from NADPH
Vitamins C and E have antioxidant roles.
Explain nitrogen balance
Most nitrogen enters the body as protein and leaves as urea. In healthy adults, there is a steady state in which the amount of N taken into the body equals the amount of N lost from the body and the individual is said you be in N balance. During periods of active growth, pregnancy and tissue repair and convalescence N intake is greater than N loss (positive N balance). There are many situations in which N intake is less then N loss (negative N balance), including starvation, malnutrition and trauma.
Explain protein turnover
All proteins undergo continuous breakdown and resynthesis i.e., they ‘turnover’. The rate of turnover depends on the protein and varies during growth (fast) and ageing (slows). The average half-life of a body protein is about 80 days. The total protein turnover in a healthy adult is around 300g-400g per day of this, 100-150g are muscle proteins and digestive enzymes. Normally the rate of protein breakdown equals the rate of resynthesis. Protein turnover is not a random process and mechanisms exist for identifying proteins that are to be degraded.
Describe how amino acids are catabolised in the body
Each amino acids have its own pathway of catabolism and thus there are 20 different pathways. However, many of these pathways share common features and all end up converting the amino acid to one or more group of molecules that are important organic precursor molecules. An early step in catabolising an amino acid is to remove the amino group which is then converted to urea and excreted in the urine.
Define the terms glucogenic and ketogenic amino acids
If an amino acid is glucogenic, it can be converted to either/ both of:
Pyruvate, oxaloacetate, fumarate, alpha ketoglutarate, succinyl CoA. They can be used to synthesise glucose or glucagon
If an amino acid is ketogenic, they can be converted to intermediates in either Acetyl CoA or acetoacetyl CoA. They can be used to synthesise fatty acids or ketone bodies.
Explain the clinical consequences of a defect in phenylamine metabolism
Usually, the first step in phenylamine metabolism is its oxidation to tyrosine by the enzyme phenylamine hydroxylase. If this is defective, phenylamine accumulates in tissues and blood. It is metabolised by other pathways to produce various products including phenylpyruvate that is excreted in the urine. This is called phenylketonuria (PKU).
Explain the clinical relevance of measuring creatine in blood and urine
A creatine blood test measures the level of creatine in the body. Creatine is a waste product that forms when creatine, which is found in your muscle, breaks down. Creatine levels in the blood can provide information on how well your kidneys are working
Describe how ammonia is metabolised in the body.
Many tissues produce ammonia, but it is toxic to cells and therefore rapidly detoxified and removed from the body. The central nervous system is very sensitive to high levels of ammonia (hyperammonaemia). The liver plays a very important role in ammonia detoxification and hyperammonaemia is seen in liver disease. Ammonia can be detoxified either by being used in the synthesis of N-compounds such as glutamine or by conversion to urea and excretion from the body. In addition, ammonia can be excreted directly from the body in the urine.
Why does PKU cause the production of phenylpyruvate and what are some of its symptoms
As the enzyme phenylalanine dehydrogenase is defective, phenylalanine accumulates in tissues and blood. It is metabolised by the other pathways to produce products such as phenylpyruvate. It is associated with brain damage as the phenylpyruvate inhibits pyruvates and interferes with energy metabolism in the brain. Also causes seizures and development delay and should be identified early.
Why does someone with PKU require a dietary source of tyrosine.
Usually, phenylalanine, dehydrogenase converts phenylalanine to tyrosine, but due to PKU it doesn’t occur. Therefore, we would require a dietary source of tyrosine even though it is a non-essential amino acid.
What is the biochemical basis behind Homocystinuria
Cystathionine B synthase has a defect to it so it no longer converts Homocysteine to Cystathionine. This means that Homocysteine concentrations remain high as well as Methionine concentration as some of the Homocysteine is converted back to Methionine
Explain paracetamol metabolism
Paracetamol is metabolised in the liver by conjunction with glucuronide or sulphate yielding relatively non-toxic metabolite. If it is a toxic dose (10g) the pathways become saturated
Then, paracetamol metabolism, produces NAQPI which is toxic to hepatocytes. It is a strong oxidising agent and undergoes conjunction with glutathione depleting the levels of it. This results in the destruction of liver cells and liver failure occurs.
