2 mechanisms of toxicity III

Question 1

what is the outline of altered cellular regulation?

Answer 1

a) altered gene expression
b) impaired ongoing cellular activity

Question 2

what is the massive graph of cell regulation (signaling)?

Answer 2

Question 3

what happens in altered gene expression?

Answer 3

i) altered transcription
ii) altered signal transduction
iii) altered signal production

Question 4

what is altered transcription?

Answer 4

-recall transcription factors: activated in cell-> binds to response elements on promoter regions of genes-> increased or decreased mRNA expression
-eg: ligand-activated transcription factors (nuclear receptor family)
-can result in inappropriate cell division (cancer), apoptosis (cell death) or proteins synthesis
-ex: endocrine disrupting chemicals (EDCs) that mimic steroid hormones (environmental hormone mimics such as xenoestrogens)

Question 5

what is altered signal transduction?

Answer 5

-growth factors and cytokines activate (phosphorylate) or inactivate (dephosphorylate) transcription factors via complex cellular signal transduction pathways
-very important in regulation of mitosis and apoptosis, and thus carcinogenesis
-another example of xenobiotics altering homeostasis or a “balance” in toxicology: “apoptosis-mitosis balance”

Question 6

what is the super complicated graph of altered signal transduction?

Answer 6

Question 7

what is altered signal production?

Answer 7

-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 8

what is impaired ongoing cellular activity?

Answer 8

xenobiotics that affect “electrically excitable cells”” (our nervous system basically)
-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 9

what is the review of autonomic (parasympathetic and sympathetic) and somatic nervous systems?

Answer 9

-acetylcholine (ACh) and norepinephrine (NE) are neurotransmitters (NT)
-ACh binds to nicotinic (N, ligand gated ion channels) and muscarinic (M, G-coupled) receptors
-NE binds to adrenergic receptors
-other NTs include serotonin and dopamine

Question 10

what are the four steps at chemical synapses?

Answer 10

1. synthesis and storage of neurotransmitter (NT) in vesicles
2. release of NT into synapse
3. activation of receptor by NT (located on adjacent neuron or effect, tissue, site)
4. inactivation of NT (AChE)

(nicotinic cholinergic system shown; steps are the same for most NTs)

Question 11

what are the goals of xenobiotics in impaired ongoing cellular activity?

Answer 11

i) altered neurotransmitter concentration in synapse
ii) altered receptor function
iii) altered action potential

Question 12

what is our main example of altered neurotransmitter concentration in synapse?

Answer 12

-organophosphorus chemicals (OPs, like pesticides) inhibit acetylcholinesterase (AChE), causing massive (global, whole body) overstimulation of nicotinic and muscarinic receptors

Question 13

what system dominates during organophosphorus poisoning (common in agriculture)?

Answer 13

PARASYMPATHETIC
-“SLUDS” (salivation, lacrimation, urination defecation, sweating) are the clinical symptoms of acute OP poisoning
-chronic, low dose exposure causes a variety of neurological and behavioral toxicities

Question 14

what do we use to treat OP poisoining?

Answer 14

atropine
-muscarinic receptor antagonist (blocks parasympathetic effects that dominate OP poisoning)
-atropine is derived from belladonna (deadly nightshade) plant (used by women in 1700s to dilate eyes)

pralidoxime (2-PAM)
-used to reactivate AChE (“pulls” OP from AChE0 (binds better to OP)

benzodiazepine
-an anxiolytic drug (ex: diazepam) used to relieve CNS anxiety and seizures

Question 15

what are other examples of altered neurotransmitter concentration in synpase?

Answer 15

-botulinum toxin
-black widow spider venom
-cocaine
-SSRIs

Question 15

what is botulinum toxin?

Answer 15

from clostridium botulinum
-binds presynaptic membrane and blocks release of ACh (from vesicles) (no ACh to bind to receptor)
-causes paralysis and death (most potent toxin known)
-used therapeutically to treat myasthenia gravis (autoimmune muscular disease) and remove “crow’s feet” (wrinkles)

Question 16

what is black widow venom?

Answer 16

-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 17

what is cocaine?

Answer 17

-blocks reuptake of NE (increases HR) causing overstimulation of adrenergic receptors
-causes heart attacks and arrhythmias

Question 18

what are SSRIs?

Answer 18

selective serotonin reuptake inhibitors (SSRIs)
-inhibit reuptake of the NT serotonin, thus increasing (serotonin) in synapses
-antidepressant drugs ex: fluoxetine (prozac)

Question 19

what are examples of altered receptor function?

Answer 19

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

-benzodiazepines, barbiturates, gamma-hydroxybutyrate (GHB, date rape drug) and alcohol activate GABA receptors, causing depressed CNS function (sedation)
-GABA (gamma-aminobutyric acid) is the major inhibitory NT in the CNS

Question 20

what are examples of altered action potential?

Answer 20

-tetrodotoxin (puffer fish, fugu) blocks Na channels on axonal membrane, abolishing action potential and blocking neurotransmission (instant paralysis)

-DDT (organochlorine insecticide) causes overstimulation of Na channels on axonal membrane, preventing repolarization and blocking neurotransmission (open long time, releasing everything)

Question 21

what is the summary of altered cellular regulation?

Answer 21

1. altered gene expression
   -transcription factors
   -signal transduction
   -signal production
2. impaired ongoing cellular activity
   -inappropriate neurotransmission due to altered NT, receptor function or action potential