Alcohol Metabolim | Oxidative Stress Flashcards
Location of alcohol metabolism
Liver 90%
Excited in urine or on breath 10%
Outline alcohol metabolism
- alcohol > acetaldehyde via alcohol dehydrogenase
- acetaldehyde > acetate via aldehyde dehydrogenase
- both steps also include NAD+ >NADH
What are the recommend limits for alcohol consumption?
14 units/week spread over at least 3 days
What causes a hangover?
Accumulation of toxic acetaldehyde
What happens to acetate after alcohol metabolism?
- added to coenzyme A to make acetyl coA
- metabolised in TCA
- utiltised for fatty acid synthesis
What are three forms of liver damage due to chronic alcohol consumption?
Fatty liver
Alcohol hepatitis
Alcoholic cirrhosis
How can liver damage lead to changes in liver metabolism
Excess NADH - decrease in NAD+/NADH ratio
Excess acetyl coA
What are the consequences of liver damage due to chronic alcohol consumption?
decrease in NAD+/NADH ratio:
- lactic acidosis
- urate crystals accumulate > gout
- hypoglycaemia
increased acetyl coA
- fatty liver
What is used to treat alcohol dependence?
How does it work?
Disulfiram
- Inhibitor of aldehyde dehydrogenase > accumulation of acetaldehyde > toxic > hangover feeling
What conditions can oxidative stress cause?
COPD
Crohn’s disease
RA
Alzheimer’s
Ischaemic injury
Cancer
Pancreatitis
Parkinson’s disease
MS
Cardiovascular disease
What is a free radical?
An atom that has 1 or more unpaired electrons + is capable of independent existence
What is used to denote a free radical?
Superscript dot
Examples of free radicals
Hydroxyl radical OH°
Superoxide O2°-
Nitric oxide NO°
Why are free radicals so damaging
Very reactive
Reactions generate a second radical > propagating damage
What are the two types of free radicals?
Reactive oxygen species
Reactive nitrogen species
How are reactive oxygen species formed
O2 + e- > superoxide O2°- > hydrogen peroxide H2O2 > hydroxyl radical OH°
How are reactive nitrogen species formed?
Superoxide O2°- + nitric oxide NO° > peroxynitate ONOO-
What are the two main types of damage to DNA of ROS
Reacts with base > modifies base causing mispairing + mutation
Reacts with sugar > strand break > possible mutation on repair
Outline the damage of ROS to proteins
- backbone > fragmentation > protein degradation
- sidechain > chains in protein structure > loss or gain of function / protein degradation
What are disulphide bonds formed between?
Thoil groups on cysteines
Outline ROS damage to lipids
Lipid peroxidation
Unsaturated lipid + FR > lipid radical
Lipid radical reacts with O2 > lipid peroxyl radical
Process repeats + chain reaction formed
3 endogenous sources of biological oxidants
Electron transport chain
Nitric oxide synthases
NADPH oxidases
Exogenous sources of biological oxidants
Radiation - UV, X ray
Pollutants
Drugs - primaquine
Toxins
How is the electron transport chain a source of ROS?
NADH and FADH2 supply e-
Sometimes e- may escape ETC and react with O2 to form superoxide
Explain how nitric oxide synthase acts as an endogenous source of ROS
Arginine > citrulline + NO°
nitric oxide synthase
Nitric oxide is toxic in high levels
What are the 3 types of nitric oxide synthase?
iNOS - inductive nitric oxide synthase
- direct toxic effect in phagocytes
eNOS - endothelial nitric oxide synthase
- produce signalling molecules
nNOS - neuronal nitric oxide synthase
- produce signalling molecules
What is respiratory burst?
- Rapid production of superoxide + H2O2 from phagocytic cells
- ROS and peroxynitrite destroy invading bacteria
- antimicrobial defence system
What does a defect in respiratory burst cause?
Chronic granulomatous disease
Cellular defences against ROS
- superoxide dismutase - converts superoxide to H2O2 and O2
- catalse - converts H2O2 into H2O and O2
- glutathoine GSH - explained on another slide
- free radical scavengers - vitamin E + C
Outline how glutathione (GSH) protects actions ROS
- GSH is oxidised by glutathione peroxidase using selenium cofactor to GSSG
- this converts H2O2 (from ROS) to H2O
- GSSG reduced back to GSH by glutathione reductase which uses e- from NADPH from PPP
Outline how free radical scavengers defend against ROS
Vitamin E - protection against lipid peroxidation
Vitamin C - role in regenerating reduced from of vitamin E
What is the rate limiting enzyme in the pentose phosphate pathway?
Glucose 6 phosphate dehydrogenase
What is a clinical sign of G6PDH deficiency?
Heinz bodies
What are Heinz bodies?
Dark staining within RBCs from precipitated haemoglobin > bind to cell membrane + alters rigidity
What does G6PDH deficiency cause?
Less NADPH
NAPDH is required to reduce GSSG to GSH
Less protection from oxidative stress
Lipid peroxidation + protein damage
Haemolysis
Outline paracetamol metabolism
- at a safe level it is broken down into glucuronide + sulphate
- at high levels it is broken down into NAPQI > direct toxic effects on protein, DNA and damage
- glutathione protects against NAPQI
What drug is used to treat paracetamol overdose?
How does it work?
Acetycystine
Replenishes glutathione levels which protects against NAPQI
How can chronic alcohol consumption cause gout?
- decreased NAD+
- inadequate NAD+ for lactate > pyruvate
- ^ lactate
- lactate competes with uric acid for excretion
- ^ uric acid levels > urate crystals accumulate
- gout
How can chronic alcohol consumption cause fatty liver?
- increased acteyl-CoA > increased synthesis of fatty acids
- decreased NAD+ > reduced fatty acid oxidation
- both cause increased synthesis of triacylglycerol
- fatty liver
How is a superoxide formed?
O2 reacts with e-
What is chronic granulomatous disease?
- Genetic defect in NADPH oxidase complex
- Respiratory burst compromised
- Causes enhanced susceptibility to bacterial infections
How does superoxide dismutase and catalase defend against free radicals?
- SOD converted superoxide to H2O2 + O2
- catalase converts H2O2 to H2O and O2
What property of aldehyde dehydrogenase limits the toxic effects of acetaldehyde?
Has a low Km of acetaldehyde
How do free radical scavengers help prevent oxidative stress?
Donate hydrogen atom + electron in ROS/RNS in non enzymatic reaction
