Toxicology Flashcards
What is LD50
Dose of xenobiotic which causes death in 50%
What is acute toxicology
Short lived
Rapid development when chemical still in body
From ST exposure
Can acute toxicology be helped by antidotes
Yes
What is chronic toxicology
Delayed toxicity after chemical left body
From LT or ST exposure
How does xenobiotic get distributed and why highly in liver
To tissues which are perfused
80% of blood goes to liver so xenobiotic in high conc
How do toxins get detoxified in metabolism
Phase II conjugation eg glutathione
Why is elimination through bile good for xenobiotic
Stops exposure of other organs
It is pre systemic elimination
What is an issue with elimination in bile
De conjugation can occur which makes them lipophillic for enterohepatic recirculation
Where does de conjugation occur other than bile
Bladder
Name some high risk organs
Lungs (high perfusion)
Kidney (high conc in filtrate)
Brain (high perfusion)
What are the 2 toxins produced by oxidative stress
Cytotoxicity
Genotoxicity
What makes ROS in oxidative stress in mitochondria
Oxidation and reduction of xenobiotics and reactive metals
Which ROS is produced by mitochondria
H2O2 hydrogen peroxide
Other than hydrogen peroxide h2o2 what other 3 ROS are there
O2- (superoxide)
O• (free radical)
OH• (hydroxyl radical)
How can O2- superoxide production get made safe
Conversion to H2o2 hydrogen peroxide
Which reaction via reactive metals can convert h2o2 into unsafe OH• hydroxyl radical
Fenton reaction
Other than conversion to h2o2 what else can O2- superoxide be converted to
RNS via reaction with NO to form peroxynitrate
How can generation of ROS in oxidative stress damage dna
It can oxidise dna bases causing mutations
What gets oxidised by ROS in proteins causing misfolding
SH disulfide
How can lipid peroxidation via ROS cause dna damage as well as membrane damage
Forms malondialdehyde which damages dna
Why does oxidative stress cause less ROS removal
Depletes glutathione
What can increased calcium via ROS cause issues
Damage to ca ATPase and cell death (apoptosis)
How does Paraquat get into cells but can’t be removed
Via polyamine transporters
Ionised so can’t leave and no efflux channels
What happens to paraquat to form a radical superoxide O-
Addition of an electron
If glutathione is at high levels what happens to the paraquat superoxide radical
Converted to H2o2 then into water
Reforms paraquat
If reduced glutathione becomes depleted from converting h202 into water via paraquat recycling what happens
Undergoes Fenton reaction and causes things like lipid peroxidation and death
What are dna binding toxins called
Genotoxins or procarcinogens
What does pro carcinogens need for activation
Metabolic enzymes
Give an example of a pro carcinogen activation by metabolic enzymes
Benzoapyrene converts to diol epoxide which binds to guanine
Benzoapyrene is converted via CYP1A1
How does aromatic amines cause dna binding / pro carcinogens
Their n acetylation and n oxidation in phase II produces nitrenium ion which binds to dna
Which toxins target acH esterase
Organophosphorus insecticides OPs
Which AA do organophosphorus insecticides bind to on ach esterase
Serine Active site
How does OP form a covalent bond with serine
Hydrolysis
How can position of hydrolysis determine if covalent bond with serine is irreversible blocking ach esterase forever
If hydrolysis occurs near serine the bond can be reversed by antidotes which promote this
If hydrolysis occurs elsewhere then bond is irreversible (aging)
Which 3 cyps promote napqi production from paracetamol
2e1
1a2
3a4
Why does overdose on paracetamol cause liver damage
No glutathione transferase to detoxify it
Napqi covalently binds to proteins and damages function causing necrosis
What treatment is given for paracetamol overdose
N acetyl cysteine (precursor for glutathione)
Where is salicylate from hydrolysis of aspirin in plasma absorbed highly
Stomach and intestines
What is salicylate metabolised into
Glycine, glucoronide, oxidised
What happens to 13% of salicylate without metabolism in liver
Excreted in kidney
What does overdose on aspirin cause
Long half life of salicylate (absorbed easy as unionised)
Slow elimination
Can’t be conjugated
How does salicylate overdose cause respiratory alkalosis
Causes hyperventilation by uncoupling OP with the tca cycle. This stops proton gradient generating ATP = hyperventilating for oxygen
How can metabolic acidosis occur via salicylate build up
More lactate due to lack of aerobic resp
The plasma ph decreases when hyperventilating which causes salicylate to unionise even more. What cns effects does it have
Neurotoxic effect
Glucose can’t be used by neurones in brain
How can salicylate overdose be treated/ stop absorption
Activated charcoal
Alkalanise urine to ionise salicylate
