Oxidative stress and alcohol metabolism Flashcards
Where is the majority of alcohol metabolised? By what and where is a small amount metabolised? Also, what two mechanisms does alcohol pass the metabolism?
In the liver
Small amount metabolised by cytochrome p450 and catalase in the brain
some lost in breath and urine
Describe the alcohol metabolism. Products, enzymes and what is produced as well>
alcohol–>acetaldehyde–>acetate
Alcohol dehydrogenase
aldehyde dehydrogenase
In the process, NAD+–>NADH
What chemical causes a hangover?
acetaaldehyde
What two things does acetate go on to do?
TCA cycle or FA synthesis
what metabolite causes liver damage. What three conditions can excessive alcohol consumption lead to?>
Acetaldehyde
Fatty liver
alcoholic hepatitis
alcoholic cirrhosis
Describe the metabolic changes that occur due to alcohol consumption (Due to two factors)
Decreased NAD+:NADH ratio
Leads to…
-Decreased conversion of Lactate to pyruvate –>increased lactate concentration of the blood–>lactic acidosis
Also increased lactate concentration–>the kidneys ability to remove uric acid to decrease–>urate crystals to build up–>gout
- Decreased NAD+ for glycerol metabolism–>Less gluconeogenesis–>Hypoglycaemia
- Less NAD+ for fatty acid oxidation–>increased synthesis of TAGs–>Fatty liver
Also increased Acetyl coA
-Increased FA synthesis–>Increased TAG–>Fatty liver
Describe a treatment for alcohol dependence?
Disulfiram
Inhibits aldehyde dehydrogenase, so acetaldehyde build up–>hangover whilst drinking
Name four diseases linked to oxidative stress
Cancer
Crohns disease
Cardiovascular disease
Ischaemic/reperfusion injury
Define free radical
an atom or molecule that contains one or more unpaired electrons and is capable of free existence
Name 3 ROS and 2 Reactive nitrogen species
ROS- Superoxide, Hydrogen peroxide and Hydroxyl radicals
RNS- Nitric oxide and peroxynitrite (ONOO-)
Two main types of damage of ROS to DNA?
ROS reacts with base–>mispairing and mutation
ROS reacts with sugar(Ie ribose or deoxyribose)–>strand break and mutation on repair
Explain how ros can damage proteins
Can damage backbone or sidechain
to backbone, can cause fragmentation–>protein degradation
to sidechain–>Can modify amino acids by eg. adding disulphide bonds, dimers, carbonyls etc..
leads to change in protein structure–>protein degradation, loss of function or gain of function
What types of groups do disulphide bonds form between?
Thiol groups on cysteine residues
What three things can inappropriate disulphide bond formation lead to?
Misfolding, cross linking and disruption of function
How can ROS damage lipids?
Free radical takes hydrogen atom from a polyunsaturated FA in the membrane lipid
Causes a chain reaction
The hydrophobic enviroment and bilayer gets disrupted and membrane integrity fails
Name three endogenous sources of biological oxidants and three exogenous sources
Endogenous: Electron transport chain
Nitric oxide synthases
NADPH oxidases
Exogenous: Radiation (EG. Cosmic rays, X-rays)
drugs
toxins
Explain how the electron transport chain can be a source for biological oxidants
NADH and FADH2 supply electron
pass through the elctron transport chain
can occasionally escape chain and react with dissolved oxygen–>superoxide
What enzyme can make Nitric oxide? What three things is nitric oxide used for? How is nitric oxide made?
Nitric oxide synthase
Arginine converted to citrulline and Nitric oxide
Nitric oxide used for: Vasodilation
neurotransmission
S-Nitrosylation
Toxic at high levels
What is a respiratory burst?
Rapid release of superoxide and Hydrogen peroxide from phagocytic cells
destroy invading bacteria
What is the cause of chronic granulomatous disease? What can this lead to?
Defect in NADPH oxidase complex
leads to enhanced susceptibility to bacterial infections
eg. Pneumonia, abscesses, impetigo, cellulitis
Name three cellular defences against ROS
Superoxide dismutase
Catalase
Glutathione
Explain how superoxide dismutase acts as a cellular defence
Converts superoxide to H2O2 and oxygen
Explain how catalase acts as a cellular defence
Converts H2O2 to water and oxygen
Explain how glutathione acts as a cellular defence
The thiol group of glutathione donates an electron to the ROS
reacts with another glutathione in the process
-the enzyme glutathione peroxidase catalyses this reaction. Forms GSSG (GSH–>GSSG)
GSSG–>GSH using glutathione reductase. Requires NADPH–>NADP+
Why is the pentose phosphate pathway important in celular defences?
Provides NADPH for the reduction of GSSG–>GSH
Enzyme Glutathione reductase catalyses this
Whhat two vitamins are important cellular defences?
vit C and E
Describe how galactosemia causes cataracts
Galactose accumulates
requires the alternative pathway to be metabolised
aldose reductase convert galactose to galactitol
uses NADPH–>NADP+
so decreased NADPH levels
so less GSSG converted back to GSH
oxidative damage to cystallin protein in the eye
Explain how a G6PDH deficiency can lead to more damage from oxidative stress
G6PDH converts 2NADP+–>2NADPH
So deficiency in this enzyme–>decreased NADPH
Decreased NADPH means less GSSG converted to GSH
so less protection to oxidative stress
What is the clinical sign of G6PDH deficiency?
Heinz bodies
What is paracetemol normally broken down to at the prescribed dose?
Sulphate and glucuronide
What builds up and causes damade in a paracetemol overdose? What type of damage does it cause?
NAPQI
Oxidative damage
What is the treatment for paracetemol overdose?
Acetylcysteine
Replenishes glutathione levels to combat oxidative stress
