Mechanisms of Toxicity III Flashcards
Altered transcription
recall transcription factors:
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)
What can altered gene expression result in?
inappropriate cell division (cancer), apoptosis (cell death) or protein synthesis
altered signal transduction
-growth factors and cytokines activated (phosphorylate) or inactivate (dephosphorylate) transcription factors via complex cellular signal transduction pathways
why is altered signal transduction very important
important in regulation of mitosis and apoptosis, and thus carcinogenesis
- another example the ‘apoptosis-mitosis balance’
________________
apoptosis ^ mitosis
altered signal production
-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)
impaired ongoing cellular activity
- xenobiotics that affect “electrically excitable cells”
-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
ACh binds to___ and ____ receptors
acetylcholine binds to nicotinic (N) and muscarinic (M) receptors
NE binds to ____receptors
norepinephrine binds to adrenergic receptors
what are two other types of neurotransmitters
serotonin and dopamine
review: four steps at chemical synapses
- synthesis and storage of neurotransmitter (NT) in vesicles
- Release if NT into synapse
- Activation of receptor by NT (located on adjacent neuron or effector [tissue] site
- Inactivation of NT
What are the targets of xenobiotics
altered neurotransmitter concentration in synapse
- e.g 1, Organophosphorus chemicals (OPs) inhibit AChE, causing massive overstimulation of nicotinic and muscarinic receptors
Parasympathetic system dominates during OP poisoning
- what are the symptoms of acute OP poisoning
“SLUDS” are the symptoms of acute
- chronic, low dose exposure causes a variety of neurological and behavioural toxicities
what does SLUDS stand for?
Salivation
Lacrimation
Urination
Defecation
Sweating
What are the three ways to treat OP poisoning
Atropine
Pralidoxime (2-PAM)
Benzodiazepine
What is Atropine
Muscarinic receptor antagonist (blocks parasympathetic effects that dominate OP poisoning)
- Atropine is derived from belladonna (deadly nightshade) plant
What is pralidoxime use to do
used to reactivate AChE (“pulls” OP from AChE)
What is Benzodiazepine
An anxiolytic drug (e.g diazepam) used to relieve CNS anxiety and seizures
What does Botulinum toxin cause to Altered NT concentration in synapse
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”
What does black widow spider venom cause with altered NT concentration in synapse
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
What is SSRIs
- and what does it inhibit
Selective Serotonin reuptake inhibitors
- inhibit reuptake of the NT serotonin, thus increasing [serotonin] in synapse
-antidepressant drugs
example 1 of altered receptor function
alpha-bungarotoxin (cobra venom) binds irreversibly to nicotinic cholinergic receptors, preventing ACh access and blocking neurotransmission
Example 2 of altered receptor function
-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
Example 1 of altered action potential
- tetrodotoxin (puffer fish [Fugu] toxin) blocks Na+ channels on axonal membrane, abolishing action potential and blocking neurotransmission
Example 2 of Altered action potential
- DDT (organochlorine insecticide) causes overstimulation of Na+ channels on axonal membrane, preventing repolarization and blocking neurotransmission
Review:
Three types of Altered gene expression
-Transcription Factors
-Signal transduction
-Signal Production
Review:
What is the impaired ongoing cellular activity
-Inappropriate neurotransmission due to altered [NT], receptor function, or action potential
