Lecture 3 - Toxicodynamics Flashcards
Non-Covalent Toxin Reactions
- Most common
- Reversible
- Involves noncovalent binding to a receptor, ion channel, enzyme
Covalent Toxin Reactions
- Irreversible
- Longer lasting, permanent
- More damaging; the target is modified and destroyed by the cell afterwards
- In a covalent rxn:
- Target is nucleophile
- Toxin is electrophile
- -> occurs via hydrogen abstractions, electron transfer, or enzymatic rxn
Therapeutic uses of botulinum toxin
- uncontrolled eye twitch
- upper motor neuron syndrome
- uncontrolled sweating
- cosmetic (botox)
Hormesis Curve
Low dose: protective - deficiency can cause blindness and infertility
Middle: right dose
High dose: toxic effects (liver damage, birth defects)
What assumptions do we make in regards to toxicity of a chemical?
- The response is due to the chemical administered (ex: air pollution - proving a link between expsoure and effect is hard - maybe the air is bad, or maybe certain populations just live in areas of lower socioeconomic status with worse environmental factors?)
- The magnitude of the response is relate to the dose
- easy to show in animal studies - Using DR relationship, there exists a precise means of expressing toxicity. This assumption is being challenged
Low Dose Effects
- Not found in standard DR curve
- difficult to regulate
- Bisphenol A: exposures that were tested below those of human exposure wer found to have major effects
- These low dose effects are effects not regulated by classical toxicological endpoints
- BaP contamination was found when researcher realized that animal supplier had switched o plasma bottles
Toxicant Intercations
Additive
Antagonistic
Synergistic 2+2=8 (one primes for the other)
Potentiation 0+2=8 (no effect + effect –> large effect)
How can toxicants disrupt proteins?
Outcome:
-Dysfunction:
–> mimic them (morphine)
–> antazgone them (flutamide)
–> Bind to proteins to prevent function (arsenic binds to tubulin to prevent assembly NOTE: ANTICANCER DRUG!)
-Neoantigen
Toxicant modifies a protein either directly or indirectly to make modified protein immunogenic in some individual. The protein becomes non-self; body starts making antibodies against it (this can be the cause of allergic rxns)
How do toxicants affect DNA?
Outcome:
-Dysfunction: interfere with template function
-..) impairing (aflataxoin) and intercalation (doxorubicin)
Destruction: cross-linking by bifunctional electrophiles (cyclophosphamide or acrolein). Can cause dna-dna crosslinks, dna-protein, etc
How do toxicants modify lipids?
-can induce lipid peroxidation initiated by hydroxyl radicals
What happens when a toxicant invades a target molecule involved in cell regulation/signaling?
- Protein synthesis is affected
- Cell division
- Apoptosis
- Neuromuscular activity and endocrine axriity are affected
What happens with a toxicant invades a taregt molecule invovled in cell maintenance?
- cell injury/cell death
- impaired integration systems
- ATP depletion and ca2+ influx
How can toxicants modify a cell/system?
-chemicals that alter pH (methanol)
-uncouplers of oxphos (2,4-nitrophenol)
-solvents, detergents which destabilize membranes
So most toxins dont act on specific receptors - they modify the environment, occupy space, interfere homeostatically
-space occupies
