Mechanisms of Toxicity III

Question 1

Altered transcription
recall transcription factors:

Answer 1

Activated in cell > bind to response elements on promoter regions of genes > increased or decreased mRNA expression
E.g. ligand-activated transcription factors (nuclear receptor family)

Question 2

What can altered gene expression result in?

Answer 2

inappropriate cell division (cancer), apoptosis (cell death) or protein synthesis

Question 3

altered signal transduction

Answer 3

-growth factors and cytokines activated (phosphorylate) or inactivate (dephosphorylate) transcription factors via complex cellular signal transduction pathways

Question 4

why is altered signal transduction very important

Answer 4

important in regulation of mitosis and apoptosis, and thus carcinogenesis
- another example the ‘apoptosis-mitosis balance’
________________
apoptosis ^ mitosis

Question 5

altered signal production

Answer 5

-increased or decreased release of hormones from endocrine glands
- also complicated due to feedback loops involved in hormone synthesis and release
- another target of endocrine disrupting chemicals (EDCs)

Question 6

impaired ongoing cellular activity
- xenobiotics that affect “electrically excitable cells”

Answer 6

-Neuronal transmission (neurotransmission)
- affects skeletal, cardiac and smooth muscle cells
- very common toxicological effects due to pesticides, drug overdoses, and natural plant/animal toxins
- also very common effects of drugs prescribed therapeutically in neuropharmacology

Question 7

ACh binds to___ and ____ receptors

Answer 7

acetylcholine binds to nicotinic (N) and muscarinic (M) receptors

Question 8

NE binds to ____receptors

Answer 8

norepinephrine binds to adrenergic receptors

Question 9

what are two other types of neurotransmitters

Answer 9

serotonin and dopamine

Question 10

review: four steps at chemical synapses

Answer 10

1. synthesis and storage of neurotransmitter (NT) in vesicles
2. Release if NT into synapse
3. Activation of receptor by NT (located on adjacent neuron or effector [tissue] site
4. Inactivation of NT

Question 11

What are the targets of xenobiotics

Answer 11

altered neurotransmitter concentration in synapse
- e.g 1, Organophosphorus chemicals (OPs) inhibit AChE, causing massive overstimulation of nicotinic and muscarinic receptors

Question 12

Parasympathetic system dominates during OP poisoning
- what are the symptoms of acute OP poisoning

Answer 12

“SLUDS” are the symptoms of acute
- chronic, low dose exposure causes a variety of neurological and behavioural toxicities

Question 13

what does SLUDS stand for?

Answer 13

Salivation
Lacrimation
Urination
Defecation
Sweating

Question 14

What are the three ways to treat OP poisoning

Answer 14

Atropine
Pralidoxime (2-PAM)
Benzodiazepine

Question 15

What is Atropine

Answer 15

Muscarinic receptor antagonist (blocks parasympathetic effects that dominate OP poisoning)
- Atropine is derived from belladonna (deadly nightshade) plant

Question 16

What is pralidoxime use to do

Answer 16

used to reactivate AChE (“pulls” OP from AChE)

Question 17

What is Benzodiazepine

Answer 17

An anxiolytic drug (e.g diazepam) used to relieve CNS anxiety and seizures

Question 18

What does Botulinum toxin cause to Altered NT concentration in synapse

Answer 18

Botulinum toxin (from Clostridium botulinum) binds presynaptic membrane and blocks release of ACh
- Causes paralysis and death (most potent toxin known)
- used therapeutically to treat myasthenia gravis (autoimmune muscular disease) and remove “crow’s feet”

Question 19

What does black widow spider venom cause with altered NT concentration in synapse

Answer 19

causes massive, explosive release of ACh (and other NTs) thus emptying vesicles
- initial overstimulation of receptors followed by no neurotransmission due to lack of ACh

Question 20

What is SSRIs
- and what does it inhibit

Answer 20

Selective Serotonin reuptake inhibitors
- inhibit reuptake of the NT serotonin, thus increasing [serotonin] in synapse
-antidepressant drugs

Question 21

example 1 of altered receptor function

Answer 21

alpha-bungarotoxin (cobra venom) binds irreversibly to nicotinic cholinergic receptors, preventing ACh access and blocking neurotransmission

Question 22

Example 2 of altered receptor function

Answer 22

-Benzodiazepines, barbiturates, Y-hydroxybutyrate (GHB) and alcohol activate GABA receptors, causing depressed CNS function (sedation)
- GABA (Y-aminobutyric acid) is the major inhibitory NT in the CNS

Question 23

Example 1 of altered action potential

Answer 23

• tetrodotoxin (puffer fish [Fugu] toxin) blocks Na+ channels on axonal membrane, abolishing action potential and blocking neurotransmission

Question 24

Example 2 of Altered action potential

Answer 24

• DDT (organochlorine insecticide) causes overstimulation of Na+ channels on axonal membrane, preventing repolarization and blocking neurotransmission

Question 25

Review:
Three types of Altered gene expression

Answer 25

-Transcription Factors
-Signal transduction
-Signal Production

Question 26

Review:
What is the impaired ongoing cellular activity

Answer 26

-Inappropriate neurotransmission due to altered [NT], receptor function, or action potential