Toxicodynamics: Mechanisms of Toxicity Flashcards
Understanding mechanisms of toxicity informs risk assessment (diagram)
Mechanisms of toxicity individual expression
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Hazard Identification Risk assessment
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Exposure
To detect to understand to predict to prevent
Four General mechanisms of toxic action
- Specific localization of xenobiotic (toxicokinetic mechanisms; e.g. tissue binding or active transport)
- Interference with critical metabolic process (e.g. neurotransmission, ATP production)
- Bioactivation to electrophiles (e.g epoxides) and increased reactive oxygen species leading to oxidative stress
- Bind to receptors (“mimicry”)
The 4 steps involved in toxicity
Toxicant
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1. Delivery (ADME)
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2a. Interaction with 2b. Alteration of
target molecule (binding biological environment
to receptor) \ /
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3. Cellular dysfunction, injury———>Toxicity
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4. Inappropriate repair and adaptation —->Toxicity
- Cellular dysfunction…
- Cellular dysfunction
- Cell signaling
~ Gene expression
~ Electrically Excitable Cells - Cell Maintenance
~Internal Maintenance
~External Maintenance
- Cell signaling
ALL = Toxicity
- Dysrepair….
- Dysrepair
- Molecular
~Protein
~Lipid
~DNA - Cellular
- Tissue
~Apoptosis
~Proliferation
- Molecular
ALL = Toxicity
Step 1: Delivery ADME
Exposure Site = ?
Absorption = ?
Distribution toward target = ?
Reabsorption = ?
Toxication = ?
What does this all lead to
Exposure site = skin, GI tract, respiratory tract, injection/bite site, placenta
Absorption = presystemic elimination (First Pass Effect [the concentration of the drug decreases before it reaches the cite of action or systemic circulation)
Distribution = Distribution away from target (entropic circulation)
Reabsorption = Excretion (tubular reabsorption - non ionized forms
Toxication = Detoxication/Detoxification (bioactivation)
Leads to the delivery of Ultimate toxicant - target molecule (protein, lipid, nucleic acid macromolecular complex)
Target site
Step 2a:
what are the three target attributes
- reactivity
- accessibility
- function
Step 2a: interaction of ultimate toxicant with target molecule
What are the 4 attributes of target molecules?
- Proteins (enzymes, receptors, structural proteins, carriers [e.g. hemoglobin], cofactors [e.g. GSH!!!!!])
- Nucleic Acids (DNA, RNA)
- Lipids (cell membranes)
- Carbohydrates - not as important
Step 2a:
What are 2 major reaction types?
Noncovalent binding and Covalent Binding
What is noncovalent binding?
- recall: hydrogen and ionic bonding, Van der Waals forces, hydrophobic interactions - weak chemical interactions
- most common reaction
- is reversible - ie hormones
e.g receptor binding, plasma protein binding
What is covalent binding
- very toxicologically relevant :(
- irreversible damage to molecule (unless repaired)
- recall: electrophiles (free radicals and epoxides)
snips double stranded DNA
What are the three minor reaction types:
- Hydrogen abstraction
- free radicals can abstracts H atoms
- X * + H-Y —> XH + Y* - Electron transfer (redox reactions)
- e.g. nitrites can oxidize Fe2+ to Fe3+ in
hemoglobin, producing methemoglobinemia - Enzymatic reactions
-e.g proteolytic snake and spider venoms (venomous enzymes are proteolytic)
Step 2a:
What are the three effects on target molecule outcomes
- Dysfunction
- Most common effects
- Usually inactivates or inhibits target molecule ie. receptors, enzymes, electron transfer chain, hemoglobin (blocks enzyme, electron transport chain) - Destruction
- e.g damage to membrane lipids (lipid peroxidation) - Neoantigen formation
- RARE; idiosyncratic
- e.g toxicant-induced autoimmune diseases such as lupus
Step 2b: Alteration of biological microenvironment;
effects NOT initiated by…
Effects NOT initiated by reaction with target molecules
e.g precipitation of ethylene glycol in kidney tubules to produce oxalic acid crystals
e.g. non-polar solvents and detergents that alter membrane lipid fluidity and disrupt ion gradients
