2 mechanisms of toxicity II

Question 1

what are very important in step 3 cellular dysfunction and injury?

Answer 1

receptors

Question 2

what are receptors?

Answer 2

-strict definition: cellular proteins that normally serve as receptors for endogenous ligands (ex: hormones, neurotransmitters, cytokines (involved in immune responses))
-broader definition: enzymes (grapefruit), transport proteins, nucleic acids (DNA), structural proteins, membrane lipids (xenobiotic “targets”)

-MANY XENOBIOTICS CAUSE THEIR EFFECT (:) OR :() BY INTERACTING WITH RECEPTORS

Question 3

what are structure-activity relationships (SAR)?

Answer 3

-the affinity of a xenobiotic for a receptors depends on its chemical structure (stereochemistry)
-stereoisomers (R,S or D,L) have the same molecular formula but can have different effects

Question 4

what does the affinity of a xenobiotic for a receptor depend on?

Answer 4

ITS CHEMICAL STRUCTURE (STEREOCHEMISTRY)
-eg: polychlorinated biphenyls (PCBs)
-ubiquitous “legacy contaminants”, highly lipophilic (log Kow values 5-8), highly toxic (“halogenated aromatic hydrocarbons”)
-209 different PCB congeners/stereoisomers 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 5

what are examples of stereoisomers with same formula but different effects?

Answer 5

-ex: dextromethorphan (cough suppressant, buy over the counter) vs levorphanol (opioid analgesic, similar to codeine)
-have none of the same side effects like constipation or addiction

-ex: stereoisomers of thalidomide

Question 6

what is thalidomide teratogenicity testing of morphological effects?

Answer 6

-timing of exposure matters a lot; windows of key growth points
-window when the baby is developing arms and legs

Question 7

what is the mechanism of action of thalidomide (teratogenicity)

Answer 7

mostly interacts with growth factors, 2 at bottom allow angiogenesis (growth of blood vessels)
-adverse outcome pathway

Question 8

what is the stereoselectivity of thalidomide?

Answer 8

Question 9

what are receptor-mediated cellular signal transduction pathways?

Answer 9

normal functions: bind appropriate ligand (ex: hormone, neurotransmitter) and propagate signal into cells

-agonist
-antagonist
-partial agonist

Question 10

what is an agonist?

Answer 10

-xenobiotics that bind to receptor and mimic the effect of the endogenous ligand
-fentanyl and codeine have same effect but need different concentrations for same effect because fentanyl has 100 times more affinity for opioid receptor

Question 11

what is antagonist?

Answer 11

-xenobiotics that bind to receptors and produce no effect (ex: inhibit or block the effect of the endogenous ligand)

Question 12

what is a partial agonist?

Answer 12

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

Question 13

what is the general diagram of receptor-mediated cellular signal transduction pathway?

Answer 13

1. G protein-coupled receptors (water soluble, cant diffuse across cell)
2. nuclear receptors (ligand activated transcription factors, lipid soluble hormones readily cross cell membrane)
3. tyrosine kinase-coupled (kinase is built into the receptor)
4. ion channel receptors (ligand activated gates)

-kinase=phosphorylates a protein
-60% of all xenos interact with G protein-coupled receptors

Question 14

what is the receptor theory?

Answer 14

the reversible interaction between xenobiotic (X) and receptor (R) follows the law of mass actions

Question 15

what is the dynamic nature of receptors?

Answer 15

-receptors can become desensitized upon continuous exposure to xenobiotic; a major mechanism of drug tolerance
-ex: desensitization of receptors is often due to downregulation (decreased receptor concentration)
-also upregulation or sensitization can occur, due to increase receptor concentration (rare)

Question 16

what has modern molecular biological techniques resulted in?

Answer 16

the discovery of many receptor subtypes where only a single type was previously thought to exist
-ex: alpha-adrenergic and beta-adrenergic receptors that bind the endogenous ligand norepinephrine (NE)
-alpha and beta adrenoceptors are furhter subdivided into a1, a2, B1, B2 and B3 (and subdivided even further)

Question 17

what is the significant of receptor subtypes?

Answer 17

tissue specificity and selectivity
-NE binding to alpha1 adrenoceptor in arteriolar smooth muscle causes vasoconstriction (a major control of blood pressure)
-NE binding to beta2 adrenoceptor in bronchiolar smooth muscle causes vasodilation (used in patients with asthma)

Question 18

what are orphan receptors?

Answer 18

receptors with no known endogenous ligand

Question 19

what are classic examples of orphan receptors?

Answer 19

-classic example is morphine; was used to characterize opioid receptors decades ago, and it wasnt until much later that we discovered the endogenous ligands for opioid receptors (endorphin, enkephalin, dynorphin)
-ex: endogenous cannabinoids that act similarly to active ingredients in cannabis plants: THC (tetrahydrocannabinol) and CBD (cannabidiol)
-ex: aryl hydrocarbon receptor (AhR) that binds xenobiotics such as PCBs, dioxins, and polycyclic aromatic hydrocarbons (PAHs)