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Detoxification & alcohol

39 important questions on Detoxification & alcohol

If you fast, insulin levels will drop and glucagon levels will rise. What happens then?

This will lead to the breakdown of proteins to get AA for gluconeogenesis.

Which AA is preferred to be broken down and why?

Alanine because it is easy to be converted into pyruvate.

If you fast you see that your urea levels increase, why?

If you fast, insulin levels will drop and glucagon levels will rise. This leads to break down of proteins in your muscle. The AA that are left contain an amine group. This amine group (NH4) is detoxified in the urea cycle.

Why do your urea levels increase and then reduce again when you start fasting?

When you start fasting your muscle proteins are being broken down, this leads to more urea. However, after a few days your body starts to realise that is should not break down all the proteins in your muscles and it switches to ketone bodies. Then the urea levels reduce again.

How is the AA metabolism regulated?

It has all to do with the concentration of the AA that you have because you can convert them into each other and into TCA cycle intermediates. This is the transamination reaction. The reaction is reversible, it can go both ways. The concentration determines in which direction the transamination will go.

What is the first step in the degradation of AA?

Donating the NH3 group to glutamate.

Why is the NH3 group preferentially transferred to glutamate?

Because glutamate can easily be deaminated via glutamate dehydrogenase to α-ketoglutarate.

What is the first step in the urea cycle? Which enzyme is needed?

In the mitochrondria the ammonium is incorporated in carbomoylphosphate. You need carbomoyl phosphate synthethase 1 (CP1) for this step.

What is the rate limiting step for the urea cycle?

The first step: formation of carbomoylphosphate.
This step depends on how much ammonia you have and on how much carbomoylphosphate you can make.

What happens after the formation of carbomoylphosphate?

Carbomoylphosphate combines with ornithine to form citrulline. Citrulline moves out of the mitochondria into the cytoplasm. There it reacts with aspartate, which brings in the second amine group, to form arginosuccinate. Fumarate can be cleaved off and you're left with arginine. As a last step you cleave off the urea from arginine and then you get back to ornithine which can move into the mitochrondria again to do it all over again.

When there are a lot of proteins degraded, you will end up with a large concentration of arginine in your cytoplasm. What does this lead to?

Arginine levels act as a stimulatory molecule. Arginine reacts with acetyl CoA to form N-acetyl-glutamate (NAG). This is a stimulator for the first reaction (NH4 to carbomoyl phosphate; in the mitochondria).

What is feedforward regulation?

This can be explained using arginine. If you have high levels of arginine the conversion of NH4 into carbomoyl phosphate is stimulated (which is the rate limiting step). So if a lot of detoxification is needed, these reactions speed up.

What is the aspartate-arginosuccinate shunt?

This shunt links the urea cycle to the citric acid cycle, and thus also the gluconeogenesis. This is possible because in the urea cycle you have fumarate and arginosuccinate, these compounds are also part of the TCA cycle.

What happens if anybody has inborn errors in the urea cycle?

This is always lethal because you have very high ammonia levels (hyperammonemia). This is acidic and will lead to acidosis and brain damage.

How can you help people with an error in the urea cycle (if they didn't die already)?

You have to get rid of an excess of AA. You can do this by taking out one of the AA. AA can always convert into other AA, so taking out one will lead to production of that specific AA from other AA. If you keep on taking this AA out, in the end an excess will be lost.

When speaking of detoxifications, what is the goal of the liver?

To generate a product that you can get rid of. Either via the urine or via the bile salts.

What are the two excretion pathways from the liver?

Water soluble --> via urine
Very hydrophobic solutes --> via bile salts

The detoxification reactions are mainly carried out by a certain family of enzymes. Which one?

Cytochrome P450 enzymes (CYP-enzymes).

What the liver wants to do is make a compounds soluble. There are three ways to do this. What are these?

Couple it to glutathione
Couple it to UDP-glucaronic acid
Couple it to phosphoadenosine phosphosulfate (PAPS)

Coupling to glutathione is dependent on glucose. Can you explain why?

Glutathione needs to be reduced to use again. To reduce it you need NADPH. NAPDH is made in the PPP from glucose.

Coupling to UDP-glucaronic acid is dependent on glucose. Can you explain why?

You make UDP-glucaronic acid from glucose.

Sometimes compounds are not soluble enough and you need to excrete it via the bile. What is an example?

Hemoglobin. This is converted to bilirubin. The bilirubin is coupled to glucuronate and can be excreted via the bile.

Some premature babies might develop jaundice. Why?

These babies have an under-developed liver. The detoxification pathway is not completely developed yet. These babies get problems with the excretion of bilirubin and that is why jaundice develops.
When the liver fully develops, this will disappear and the baby is completely healthy.

What is the basic breakdown scheme of ethanol?

Alcohol dehydrogenase converts ethanol to acetaldehyde. This is converted to acetate via acetaldehyde dehydrogenase. Acetate is converted into acetyl CoA.

What is the toxic compound in the breakdown of ethanol?

Acetaldehyde

Why do you get a hangover when you drink alcohol?

Ethanol is converted into acetaldehyde. This is the toxic compound. The conversion of acetaldehyde into acetate is the slowest reaction. This leads to accumulation of acetaldehyde and this gives you the hangover.

Why do (many) people from Asia have a lower alcohol tolerance?

Because of a mutation (or polymorphism) in the acetaldehyde dehydrogenase enzyme.

Beside the build up of acetaldehyde there is another problem when drinking alcohol. What is this problem?

NADH levels also rise. If you have a high level of NADH the TCA cycle will stop. Then there are two things you can do: make FA or make lactate. If you convert pyruvate into lactate this will regenerate NAD+. However, lactate is acidic so this will lead to lactate acidosis

Why do people that drink a lot develop a fatty liver?

Acetaldehyde destroys tubulin, therefore the formation of VLDL particles is blocked. Since there is less VLDL, the FA cannot be transported to the tissues and they stay in the liver. This leads to the fatty liver.

What is the consequence of a fatty liver?

This leads to inflammation, this activates Kupfer cells and stellate cells.

What are Kupfer cells and what is the relation with stellate cells?

Kupfer cells are macrophages that are activated by products that have been peroxydized by acetaldehyde. The activated Kupfer cell excretes all kinds of radicals but also cytokines. These products activate the stellate cells. The stellate cells think that there is some kind of a wound and they start to make all kinds of matrix proteins to repair the wound. This will lead to fibrosis and scar tissue inside the liver.

What is the problem if you don't eat before you drink?

Because the gluconeogenesis is blocked, no new glucose is made and this leads to hypoglycemia. Since there is no glucose left, your body can only make ketone bodies and this leads to keto-acidosis.

What is the problem with acidification of your blood?

If your blood gets acidified your erythrocytes are prevented from exhaling CO2. This leads to heavy breathing and it can lead to a coma.

What is the effect of chronic alcohol use on liver detoxification?

Your body upregulates the CYP enzymes, especially the microsomal ethanol oxidizing system (MEOS) (CYP2E1). This will convert ethanol into acetaldehyde, using NADPH and generating NAD+. The accumulation of acetaldehyde will be even faster now.
This CYP2E1 will also produce some ROS. So, it's not beneficial to have this upregulation.

What is the danger of alcoholics and painkillers?

Painkillers can be degraded by the MEOS system. This system is upregulated in severe alcoholics. You form NAPQI which is very toxic. If you want to get rid of this you need glutathione. However, glutathione is needed to prevent radical damage. So your ROS is increased. This can lead to paracetamol poisoning.

There are two pathways leading to a blood clot. What are these and what is the difference?

Extrinsic and intrinsic pathway. The intrinsic pathway uses components that are all in the blood and the extrinsic pathway uses tissue factor, which is released from damaged cells.

Platelets bind to coagulation factors. Where are these coagulation factors made and why are they needed?

Coagulation factors are made in the liver. These factors have an important posttranslational modification: γ-carboxylation.

What is γ-carboxylation? What does this reaction depend on?

A carboxylase enzyme transfers glutamate into carboxyl glutamate. This reaction is dependent on vitamin K.

What is the effect of alcohol on blood clotting?

Alcohol prevents the carboxylation reaction and this causes blood thinning.

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Medical Biochemistry

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