Mechanisms of toxicity II Flashcards
What is the strict definition of Receptors?
Strict definition: Cellular proteins that normally serve as receptors for endogenous ligands (e.g hormones, neurotransmitters, cytokines)
What is the broader definition of Receptors?
Enzymes, transport proteins, nucleic acids, structural proteins, membrane lipids (xenobiotic “targets”)
Many xenobiotics cause their effects (:) and :() by interacting with receptors
What is SAR
Structure-activity relationships (SAR)
- The affinity of xenobiotic for a receptor depends on its chemical structure (stereochemistry)
- Stereoisomers (R,S or D,L) have the same molecular formula but can have very different effects (e.g dextromethorphan [cough suppressant] vs. levorphanol [opioid analgesic, similar to codeine])(e.g stereoisomer of thalidomide)
what is an example of SAR
polychlorinated biphenyls (PCBs)
- ubiquitous “legacy contaminants”, highly lipophilic (log Kow values 5-8), highly toxic (“halogenated aromatic hydrocarbons”)
How many different PCBs are there?
209 different PCB congeners that differ in the number and location of chlorine atoms and differ in toxicity by over 1000-fold
- why? affinity for the aryl hydrocarbon receptor (AhR) determines toxicity of individual PCB congeners
Thalidomide Teratogenicity: Morphological effects
Timing of dose, effects outcomes, effects arm growth, head growth etc.
What genes are a part of the mechanism of action in Thalidomide teratogenicity
IGF-1-Gene,
IGF-1-receptor-gene
av-gene
FGF-2-gene
FGF-receptor-gene
B3-gene
integrin avB3
Angiogenesis (development of blood vessels)
What are normal functions of receptor-mediated cellular signal transduction pathways
Bind appropriate ligand (e.g. hormone, neurotransmitter) and propagate signal into cell
What is Agonist
xenobiotics that bind to receptor and mimic the effect of the endogenous ligand
What is Antagonist
xenobiotics that bind to receptor and produce no effect (ie. inhibit or “block” the effect of the endogenous ligand)
What is partial agonist
xenobiotics that bind to receptor and produce a lesser effect than the endogenous ligand
What are the four different receptor-mediated cellular signal transduction pathways?
- G protein-coupled receptors
- Nuclear receptors
- Tyrosine kinase-coupled receptors
- Ion channel receptors
What is the receptor theory
The reversible interaction between xenobiotic (X) and receptor (R) follows the law of mass action and is represented by
[X] + [R] <-> [XR] -> Effect
Where [XR] is the concentration of activated xenobiotic-receptor complexes
Receptors can become ___ upon continuous exposure to____
Receptors can become desensitized upon continuous exposure to xenobiotic; a major mechanism of drug tolerance
Desensitization of receptors is often due to…
downregulation (decreased receptor concentration)
main response from ligand receptors
what rare occurrence can happen due to the increased receptor concentration
upregulation or sensitization
What is an example of receptors that bind the endogenous ligand norepinephrine (NE)
alpha-adrenergic and Beta-adrenergic receptors
what are alpha and Beta adrenoceptors further subdivided into?
a1, a2, B1, B2, B3 (and subdivided even further)
moderns molecular biological techniques have resulted in the discovery of many receptor subtypes where only a single type was previously thought to exist
What is the significance of receptor subtypes
Tissue specificity and selectivity
NE binding to a1 adrenoceptor in ______smooth muscle causes what?
-arteriolar smooth muscle
-vasoconstriction (a major control of blood pressure)
NE binding to B2 adrenoceptor in ____ smooth muscle causes what?
-bronchiolar smooth muscle
-vasodilation (used in patients with asthma)
What are orphan receptors
receptors with no known endogenous ligand
what is a classic examples of an orphan receptor
morphine (a xenobiotic) used to characterize opioid receptors decades ago
what are three happy hormones (dopamine hormones)
endorphin, enkephalin, dynorphin
what is AhR
Aryl hydrocarbon receptor (orphan receptor)
it binds to xenobiotics such as PCBs, dioxins and polycyclic aromatic hydrocarbons (PAHs)
what do PAHs do
changes gene receptors
