Toxicity Mechanisms Flashcards
What are the modifying factors of toxicity?
- Dose
- Duration and frequency of exposure
- Species, strain, individual
- Gender, pregnancy
- Age
- Nutritional status
- Disease
- Physical (environmental) factors
- Social factors
what are idiosyncrtic responses/reactions?
toic effects with no known cause; have a genetic component;
what are the 4 general mechs of 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 reactive oxygen species)
- Bind to receptors (“mimicry”)
Mechanisms of toxicity: toxicokinetics=dose toxicodynamics=response
–toxicodynamics is how the xeno interacts with a target molecule
ya
rxn types
noncov binding; cov binding; hydrogen abstraction; electron transfer; enzymatic rxns
what is noncov binding?
a. Weak interacions; H-bonds, vdWs
b. Reversible
c. E.g. xenos to plasma protiens, to receptors and enzymes
what is cov binding?
a. Very strong, share e’s
b. “irreversible”
c. CYP will make an epoxide, which is a reactive metabolite and the O will covalently bind to DNA nts
d. When enzyme goes to replciate DNA, it won’t be able to because of the epoxide blocking
what is hydrogen abstraction?
a. Pulling H off of a molecule
what are enzymatic rxns?
a. E.g. snake venoms
b. Can cause proteolytic proteins to activate and break down other proteins
what are the main effects on target molecules?
dysfunction or altered function; destruction; or neoantigen formation
what is dysfunction or altered function?
○ E.g. dysfunction of DNA molecule due to xeno binding to DNA
○ When xenos interact with receptors may alter function
○ Enzymes involved In critical functions
§ E.g. electron transport chain
what is destruction?
○ E.g. suicide inhibition–> destroys the enzyme for good
○ “irreversible” covalent interaction, changes conformation of enzymes so it can no longer work
what is neoantigen formation?
“neo” =new, “antigen”–>stimulates Ab response/production
○ Can bind to receptor and stimule Ab response to start killing self-molecules
○ Xenos can be the main problem for autoimmune diseases
Usually indiosyncratic
what is the definition of receptors?
Strict definition: Cellular proteins that normally serve as receptors for endogenous ligands (e.g., hormones, neurotransmitters, cytokines)
Broader definition: Enzymes, transport proteins, nucleic acids, structural proteins, membrane lipids (xenobiotic “targets”)
structure affects toxicity–affinity of a xeno can be altered by modifying something about it–> isomerizing it; adding another chlorine; may make it 1000x more or less toxic
ya
e.g. of isomers of xenobiotics with very different effects
e.g., dextromethorphan (cough suppressant) vs. codeine e.g., stereoisomers of thalidomide
what is GPCR?
H--hormone, first messenger G-proteins--transducers Effector: AC cAMP is the second messanger Activates kinases-->phosphorylates proteins-->activates protein-->amplification Oer half of all xenos act through GPCRs --can also change gene transcription
what are nuclear receptors?
Nuclear receptor super family
H goes direct into cell, is lipophilic–steroid, thyroid hormones
Affect gene transcription–R might be on the gene to turn on transcription
–ligand activated transcription factors
—has more long-term effects bc it changes proteins and whatnot
Tyrosine kinase receptor general info
ATP stimulates TKCR–phosphoryaltes protein
E.g. insulin and growth hormone binds to these receptors
Similar to GCPR (protein phos/act)–through different method
ion channel general info
Control mainly Na and Cl’s ability to move in and out of cells
–gates for ions; normally closed; when hormone binds, changes conf, opens, ions rush in–AP generation
roles xenos can play with receptors
agonist, antagonist, partial agonist; endocrine disruptors
what are agonists?
○ Binds to receptor and mimics endogenous ligand
Produces a full response
What are antagonistic xenos?
○ Binds to receptor but produce no response
§ Blockers–beta blockers
Competitive (binds to receptor) or noncomp (binds to site other than receptor–changes conformation?)
what are partially agonistic xenos?
○ Binds to receptor but produces a lesser response
○ Based on the affinity for the partial agonist for the receptor
○ Agonist is like a light switch–>turn it on, lights up–>partial ag. I like a dimmer switch–>less of a response
what are endocrine disruptive xenos?
○ Xenos can interfere with endocrine system and function in us
○ Act as partial ags
Most are able to mimic steroid hormones, lipophilic, can interact with nuclear receptors, alter gene expression
what is receptor theory?
• [xeno]+[receptor] determines [XR] which determines the effect
receptor subtypes
• Adrenergic receptors–endogenous ligand is NE
○ Have both alpha (1,2) and beta (1,2) subtypes
§ Subtypes of subtypes
what are alpha 1 receptor subtypes?
§ A1 adrenergic receptors are highly expressed on arterioles–main vasculature which control vasodilation and constriction
When NE binds, causes cells to contract and control BP
what are beta 2 receptor subtypes?
§ B2 present in bronchioles
□ Smooth muscle cells (same in artioles) contain lots of B2
□ When an NE bidns to a B2, you get relaxation of smooth muscle cells, allowing bronchioles to open
□ Used in asthma–have constriction in bronchioles
what are orphan receptors?
• Receptors with no known endogenous ligand
• Opiates
• Morphine binds to opioid receptors (also have subtypes)
○ Fetanyl is 100 times more potent than morphine–means it binds to 100 times more tightly to receptors–will have 100 times the effect
• E.g. cannabinoid receptors
○ Bind THC (tetrahydracannabinol??)
○ Don’t know what the endogenous ligand is–we have endogenous ligands in our brain which produce a similar effect to THC
§ may be involved in hunger
• E.g. aryl hydrocarbon receptor (AhC)
symptoms of OP poisoning
SLUDS– ○ Salivation, lacrimation, urination, defecation
○ OPs stimulate GI tract (defecation), fluid release
Most responses are due to overstim of muscarinic receptors (parasym receptor)
OP overdose treatment
• Can use atropine as a treament
○ Antagonist of muscarinic receptor (blocker)
From belladonna alkaloids–used to be taken to dilate pupil
• Pralidoxine (2-PAM)
○ OPs Bind to ACh-esterase–inactivate
○ 2-PAM Reactivates enzyme –pulls OP off of enzyme
• Benzodiazepene (BDZ)
○ OP poisoning leads to excitement/anxiety–BDZ relaxes them
