Alcohol metabolism and ox stress Flashcards
Where is alcohol metabolised
90% metabolised in liver
remainder excreted passively by urine or breath
what is the recommended unit limit of alcohol a week
14 units for both men and women spread over at least three days
what is the rate of alcohol metabolism
7g per hour
how many grams is one unit of alcohol
8g
what does is mean that rate of alcohol metabolism is zero order
means that a change of conc does not change rate
what is the first step and enzyme in alcohol metabolism
Enzyme: alcohol dehydrogenase
alcohol converted to acetaldehyde using NAD to produce NADH
why is a build up of acetaldehyde a problem
it is toxic so causes hangover like symptoms
what does it mean that alcohol dehydrogenase is low specificity
low Km so high affinity even at low concs
what is the second enzyme and step in alcohol metabolism
enzyme: aldehyde dehydogenase
converts acetaldehyde to acetate using NAD to NADH which is then conjugated to CoA
what can a small amount of alcohol by metabolised by
cytochrome P450ZE1 or catalase in the brain
how can excessive alcohol consumption damage the liver membranes and what enzymes appear in blood to show this
- pathways saturated so acetaldehyde accumulates which is toxic
- this causes liver cells to have more leaky membranes which causes a loss of enzymes (enzymes like transaminases and gamma glutamyl transpeptidase appear in blood )
how is the damaged liver from alcohol consumption not able to function
- reduced ability to take up billirubin leading to hyperbillirubinaemia leading to jaundice
- high ammonia and glutamate
- low albumin levels, lotting factors and lipoproteins so lipids synthesised in liver cannot be transported out –> fatty liver
how does alcohol oxidation affect liver metabolism by having increased acetyl CoA
increased synthesis of fatty acids and ketone bodies so more triacylglycerols more fatty liver
how does alcohol oxidation affect liver metabolism by having decreased NAD
- not enough NAD for conversion of lactate to pyruvate so lactate accum in blood –> lactic acidosis and kidney has same transporters for lactate and urea so saturated with lactate so urea builds up –> gout
- inadequate NAD for glycerol metabolism so deficit in gluconeogenesis leading to hypoglycaemia
- not enough NAD for fatty acid ox so more triacylglyerols
how does excess alcohol affect GI tract
- damage to cells lining GI
- low appetite, diarrhoea, impaired absorption (vit K, folic acid, pyridoxine, thiamine –> Korsakoff’s)
- chronic pancreatitis
what is disulfiram
a drug that is used as a adjunct to treat chronic alcohol dependence
describe the mechanism of disulfiram
- inhibits the enzyme aldehyde dehydrogenase
- accumulation of acetaldehyde
- symptoms of hangover –> classical conditioning
what is a free radical
any atom or molecule or ion that has one or more unpaired electrons and capable of independent existence
what are properties of free radicals
- very reactive
- tend to acquire electrons from other molecules causing damage and generating new radicals = chain reaction
how is the ROS superoxide formed
oxygen + e –> superoxide
why is oxygen considered a biradical
has two unpaired electrons
how do ROS damage DNA when reacting with a sugar
cause strand breaking or mutation leading to cancer
how do ROS damage DNA when reacting with a base
cause mispairing and mutation leading to cancer
how do ROS damage proteins when reacting with the sidechain
modified AA gives rise to diff structure which leads to loss of function degradation, gain of new function
how do ROS damage proteins when reacting with the backbone
fragmentation of backbone leads to protein degredation
how do ROS cause damage by forming disulphide bonds
- ROS can cause extra disulphide bonds
- form between thiol groups of cysteine residues
- ROS takes electrons from cysteines causing misfolding and cross linking
how do ROS damage lipids
- free radical extract H+ from polyunsaturated FA in mem which forms a radical which can react with oxygen to lipid peroxyl radical = chain reaction of lipid peroxidation
- causes damage to hydrophobic bilayer of mem so integrity of mem fails
what are the endogenous sources of ROS
- ETC electron escapes and reacts with oxygen
- peroxidases
- nitric oxide synthases
- lipooxygenases
- NADPH oxidases
- xanthine oxidase
- monoamine oxidase
what are some exogenous source of ROS
- Radiation (UV, cosmic, X- rays)
- pollutants
- drugs (primaquine)
- toxins (paraquat)
lists the ROS
- superoxide
- hydrogen peroxide
- hydroxyl radical
list the RNS
- peroxynitrite
- nitric oxide
how is hydrogen peroxide formed
superoxide + 2H+ + e –> H2O2
how is the hydroxyl radical formed
H2O2 + e + H+ –> H2O + OH
how is nitric oxide formed
- from arginine and NADPH and O2 using nitric oxide synthase
what are the three isoforms of nitric oxide synthase
- iNOS ( inducible) : produced high NO in phagocytes for resp burst
- eNOS ( endothelial): signalling
- nNOS (neuronal) : signalling
how is peroxynirite formed
nitric oxide reacts with superoxide to produce peroxynitrite
what is the respiratory burst
rapid production of superoxide and H2O2 from phagocytic cells so ROS and peroxynitrite can destroy bacteria invading cells
describe the process of respiratory burst
- phagolysosome engulfs invading bacteria
- NADPH oxidase converts NADPH + O2 –> NADP and forms superoxide which converts to H2O2
- superoxide reacts with nitric oxide made by iNOS to form peroxynitrite
- H2O2 reacts with Cl- catalysed myleoperoxidase to make hypochlorite
- hypochlorite and peroxynitrite destroy invading bacteria
how does the enzyme superoxidase dismutase protect against ROS
converts superoxide to H2O2 and O2
- primary defence (especially in ETC) as superoxidase is strong inhibitor
- 3 isoforms
how does catalase protect against ROS
converts H2O2 to water and oxygen
- important in immune cells to protect against widespread burst
what is glutahtione
a tripeptide synthesised by body to protect against ox damage
what three AA make up glutathione
gly- cys- glu
how does glutathione protect against ox damage using what enzyme
thiol group on cys donates electron to ROS then reacts with another GSH forming disulphide bonds (GSSG) catalysed by enzyme glutathione peroxidase which requires selenium
how is GSSG reduced back to GSH
GSH is reduced active form so converted using enzyme glutathione reductase which transfers electrons from NADPH ( from PPP) to disulphide bond
what are free radical scavengers
reduce free radicals damage by donating hydrogen atoms and an electron to free radicals in nonenzymatic reaction
name the free radical scavengers
- vitamin E
- vitamin C
- carotenoids
- flavonoids
- uric acid
- melatonin
how is ox stress caused in galacosemia
- deficiency in an enzyme in galactose pathway
- build up of galactose converted to galacticol by aldose reductase consuming excess NADPH
- lower NADPH means less defence from ROS and cannot convert GSSG back to GSH
- disulfide bonds form in lens
how does a deficiency in G6PD enzyme relate to ox stress
G6PD enzyme in PPP so no NADPH formed so GSSG cannot be converted to GSH so less protection
how are heinz bodies formed
- ROS cross links Hb forming aggregates
how is paracetamol normally metabolised
broken down in liver to glucuronide and sulphate
what happens to paracetamol metabolism when overdosing
normal pathway saturated so go down NAPQI pathway which is directly toxic (ROS) to cells and depletes cells of glutathione causing more ox damage
what is the antidote for paracetamol overdose and how does it work
- acetylcysteine
replenishes glutathione levels to protect against ox stress
