Mechanisms of toxicity II

Question 1

What is the strict definition of Receptors?

Answer 1

Strict definition: Cellular proteins that normally serve as receptors for endogenous ligands (e.g hormones, neurotransmitters, cytokines)

Question 2

What is the broader definition of Receptors?

Answer 2

Enzymes, transport proteins, nucleic acids, structural proteins, membrane lipids (xenobiotic “targets”)

Many xenobiotics cause their effects (:) and :() by interacting with receptors

Question 3

What is SAR

Answer 3

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)

Question 4

what is an example of SAR

Answer 4

polychlorinated biphenyls (PCBs)
- ubiquitous “legacy contaminants”, highly lipophilic (log Kow values 5-8), highly toxic (“halogenated aromatic hydrocarbons”)

Question 5

How many different PCBs are there?

Answer 5

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

Question 6

Thalidomide Teratogenicity: Morphological effects

Answer 6

Timing of dose, effects outcomes, effects arm growth, head growth etc.

Question 7

What genes are a part of the mechanism of action in Thalidomide teratogenicity

Answer 7

IGF-1-Gene,
IGF-1-receptor-gene
av-gene
FGF-2-gene
FGF-receptor-gene
B3-gene
integrin avB3
Angiogenesis (development of blood vessels)

Question 8

What are normal functions of receptor-mediated cellular signal transduction pathways

Answer 8

Bind appropriate ligand (e.g. hormone, neurotransmitter) and propagate signal into cell

Question 9

What is Agonist

Answer 9

xenobiotics that bind to receptor and mimic the effect of the endogenous ligand

Question 10

What is Antagonist

Answer 10

xenobiotics that bind to receptor and produce no effect (ie. inhibit or “block” the effect of the endogenous ligand)

Question 11

What is partial agonist

Answer 11

xenobiotics that bind to receptor and produce a lesser effect than the endogenous ligand

Question 12

What are the four different receptor-mediated cellular signal transduction pathways?

Answer 12

1. G protein-coupled receptors
2. Nuclear receptors
3. Tyrosine kinase-coupled receptors
4. Ion channel receptors

Question 13

What is the receptor theory

Answer 13

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

Question 14

Receptors can become ___ upon continuous exposure to____

Answer 14

Receptors can become desensitized upon continuous exposure to xenobiotic; a major mechanism of drug tolerance

Question 15

Desensitization of receptors is often due to…

Answer 15

downregulation (decreased receptor concentration)
main response from ligand receptors

Question 16

what rare occurrence can happen due to the increased receptor concentration

Answer 16

upregulation or sensitization

Question 17

What is an example of receptors that bind the endogenous ligand norepinephrine (NE)

Answer 17

alpha-adrenergic and Beta-adrenergic receptors

Question 18

what are alpha and Beta adrenoceptors further subdivided into?

Answer 18

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

Question 19

What is the significance of receptor subtypes

Answer 19

Tissue specificity and selectivity

Question 20

NE binding to a1 adrenoceptor in ______smooth muscle causes what?

Answer 20

-arteriolar smooth muscle
-vasoconstriction (a major control of blood pressure)

Question 21

NE binding to B2 adrenoceptor in ____ smooth muscle causes what?

Answer 21

-bronchiolar smooth muscle
-vasodilation (used in patients with asthma)

Question 22

What are orphan receptors

Answer 22

receptors with no known endogenous ligand

Question 23

what is a classic examples of an orphan receptor

Answer 23

morphine (a xenobiotic) used to characterize opioid receptors decades ago

Question 24

what are three happy hormones (dopamine hormones)

Answer 24

endorphin, enkephalin, dynorphin

Question 25

what is AhR

Answer 25

Aryl hydrocarbon receptor (orphan receptor)
it binds to xenobiotics such as PCBs, dioxins and polycyclic aromatic hydrocarbons (PAHs)

Question 26

what do PAHs do

Answer 26

changes gene receptors