MEH Alcohol metabolism and oxidative stress Flashcards by RG Cattermole

Where is most alcohol metabolised in the body?

90% liver

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Where does the other 10% go?

Breath

Kidneys

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What common molecule does alcohol metabolism form?

Acetyl co A

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What is the recommended drinking limits for men and women in UK?

14 units a week over at least 3 days

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Why two enzymes are used in alcohol metabolism? Why by produce causes a hangover?

Alcohol dehydrogenase (alcohol to acetyl aldehyde)
Aldehyde dehydrogenase  (acetyl aldehyde to acetate)
Toxic metabolite intermediate acetyl aldehyde responsible for hangover

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How is acetate converted to acetyl co A? What happens after that in metabolism?

Bound to co enzyme A

Used in TCA cycle or for fatty acid synthesis

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Which metabolite of alcohol can lead to liver damage? What by products of alcohol metabolism can change liver metabolism?

Acetyl aldehyde

NADH and acetyl co A

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Alcohol oxidation leads to (increased/decreased) NAD+ and (increased/decreased) acetyl co A?

Alcohol oxidation leads to reduced NAD+ as carrier molecule has taken e-/H+ from oxidation reactions.

Increase in acetyl co A from acetyl aldehyde

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What are the the three initial consequences of low NAD+? What is the initial consequence of increased acetyl co A build up?

Reduced NAD+ means less substrate for

Conversion of lactate to pyruvate
Metabolism of glycerol
Fatty acid oxidation

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What four consequences can occur as a result of reduced NAD+ for conversion of lactate to pyruvate?

Lactic acidosis
Reduced gluconeogenesis - hypoglycaemia
Urate crystals accumulate in tissues producing gout
Also reduced FA oxidation which adds to fatty liver

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How does alcohol excess lead to gout?

Alcohol oxidation causes a decrease in NAD+, so there is less substrate to convert lactate to pyruvate (oxidation), meaning there is a lactate build up. This reduces the kidneys ability to excrete uric acid - uric acid builds up in tissues producing gout

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How does alcohol excess lead to hypoglycaemia?

Reduced NAD+ availability due to alcohol oxidation, leads to less substrate for metabolism of glycerol in the liver. So less gluconeogenesis in the liver —> hypoglycaemia

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How does alcohol excess lead to lactic acidosis?

Reduced NAD+ due to alcohol oxidation leads to less lactate being converted to pyruvate in the liver. Lactate accumulates –> reduced pH in blood lactic acidosis

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What are the three methods that lead to fatty liver in alcohol excess?

Reduced NAD+ due to alcohol oxidation means inadequate NAD+ for fatty acid oxidation –> build up of FA leads to increased TAGs that are stored/deposited in liver.

Also increased acetyl co A from alcohol oxidation from acetyl aldehyde leads to diversion of acetyl co A to form ketone bodies and FA –> increased TAGs

Lower lipoprotein synthesis so fat accumulates as can’t make amino acids/proteins

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What can increased acetyl co A from alcohol metabolism lead to?

Increased FA synthesis and ketones —> increased TAG synthesis leading to fatty liver

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What is dilsufuram and how is it used?

Is a drug that blocks aldehyde dehydrogenase, so acetyl aldehyde accumulates giving symptoms of hangover.

Is used in conjunct as a therapy for alcoholism

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Which 3 main molecules in the body can ROS disrupt?

DNA
Proteins
Lipids

How can ROS disrupt DNA (2 main ways)

Damage to base

- Damage to sugar

What can a DNA damaged base or damaged sugar lead to? Why ultimate disease can this cause

Base - mispairing - mutations
Sugar (backbone) - DNA break and mutation on repair

Cancer

What is 8-oxy-dG? How is this used clinically?

One of the major products of DNA ROS - can be used to measure the amount of oxidative damage in a cell

How can ROS damage proteins (2 major ways)

Backbone

- Side chain

What happens if the backbone vs side chain are damaged by oxidative stress in proteins?

Backbone - protein fragmentation and degradation

Side chain - increase or decrease of function due to a change in structure - in particular disulphide bonds

How can disulphide bonds caused by oxidative damage lead to disruption of protein function?

Can cause misfolding, cross linking which can change the structure and therefore function of the protein.

What is the major way that oxidative damage can disrupt lipids (i.e. phospholipid membranes)?

Lipid peroxidation - hydroxyl radicals extract a hydrogen from fatty acid tail of polyunsaturated fatty acid, lipid radical formed that can react with O2 to form a lipid peroxyl radical. This forms chain reaction as lipid peroxide then extracts hydrogen from nearby fatty acid. Hydrophobic environment of lipid bilayer disrupted and membrane integrity fails.

Name 3 major endogenous sources of ROS and 3 exogenous. Which is the main source of ETC? How?

ETC - main one - O2 at the end of the chain can become a radical and cause damage NO synthase NADPH oxidases

How can the ETC produce free radicals?

In the ETC sometimes instead of H+/e- being combined with O2 at the end in a controlled reaction to produce water, the H+ ions escape and react with O2 to form superoxides.

How can enzymes e.g. Nitric oxide synthases produce free radicals? How many types of NOS are there and what are they used for?

3 types - iNOS (used by phagocytes) eNOS (endothelial) nNOS (neuronal signalling) Form nitric oxide which is a vasodilator/signalling molecule but is toxic at high levels.

Which 2 mechanisms do neutrophils use to kill bacteria via respiratory burst? Which 3 enzymes?

1) NADPHoxidase donates an electron to O2 to produce superoxide 2) iNOS forms nitric oxide 3) 1 and 2 combine to form OONO- peroxynitrite 4) Myeloperoxidase is also secreted in granules and forms HOCl (hypochlorite) Hypochlorite and peroxynitrite are used to kill bacteria

What can happen if you have a genetic defect in the enzyme NADPHoxidase?

``` Prone to infection - Pneumonia Cellulitis Accesses Impetigo Atypical infections ```

Which 4 defence systems (from the lecture) does the body have against oxygen free radicals?

- Superoxide dismutase - Catalase - GSH (Glutathione) - Free radical scavengers

How does SOD and catalase reduce free radicals? Which cells would you find catalase?

SOD converts superoxide radicals into hydrogen peroxide (H2O2) and oxygen. Catalase then converts hydrogen peroxide into water and oxygen. Catalase widespread but important in immune cells to protect against oxidative burst

Which free radical is a strong initiator of oxidative damage chain reactions?

Superoxide

How does glutathione protect against oxidative damage? What enzyme is needed for this and what essential trace element is needed for the enzyme to work?

It donates an e-/H+ to a ROS Two glutathione then form disulphide bonds with each others cysteine residues. Glutathione peroxidase is the enzyme and it requires selenium to work.

How is the pentose phosphate pathway essential for protection against free radical damage? What enzyme is used for this process?

The NADPH from PPP is used to covert reduced GSSG (two glutathiones joined with the disulphide bond) back to GSH (glutathione) - by glutathione reductase.

Which vitamins are free radical scavengers and how do they work? Are enzymes involved?

Vit E - lipid soluble antioxidant, important for protection against lipid per oxidation Vit C - ascorbic acid - water soluble antioxidant, important for regenerating reduced form of Vit E. Free radical scavengers reduce oxidative damage by donating an electron to the free radical in a non enzymatic reaction

How does gallctossamia lead to cataracts (think ROS)

Build up of galactose increased activity of aldose reductase reduces NADPH Compromised ROS defences - glutathione defence Crystallin protein in lens of eye denatured by ROS Cataracts

How does G6PDH deficiency lead to heinz bodies (think ROS)

Reduced G6PDH leads to decreased NADPH being formed - compromises the glutathione defence - ROS - leads to lipid per oxidation deforming cell membranes, and protein misfolding - aggregates of cross-linked Hb = heinz bodies - haemolytic anaemia

What are blister cells and what are they a sign of?

Spleen removes Heinz bodies from RBC resulting in 'blister cells' - is a clinical sign to diagnose G6PDH

What is NAPQI and how can it leave to oxidative damage in liver cells?

NAPQI is a toxi metabolite of paracetamol. It directly causes oxidative damage of liver cells, but also conjugates to glutathione in the liver, depleting the livers reserves so wiping out one of the liver's defence mechanisms against oxidative damage = 2 inputs cause damage that is irreversible.

What types of oxidative damage can occur in liver cells? (any cells)

- DNA damage - Protein damage - Lipid peroxidation

What is the treatment for paracetamol overdose?

Acetylcycsteine - works by replenishing glutathione levels