Lecture 3- Basic mechanisms of Toxicants 1

local effect

the site of action takes place at the point of contact

what are examples of the site of action

skin surface

mucous membrane of the eyes, nose, mouth, throat

or anywhere that along the respiratory or GI system

systemic effect

the toxic substance has been absorbed and distributed throughout the body

cumulative effect

factors affecting toxicity

routes of entry

percutaneous

inhalation

oral

ocular

mechanisms of toxicity

1. Delivery: Site of Exposure to the Target

2. Reaction of the Ultimate Toxicant with the

Target Molecule

3. Cellular Dysfunction and Resultant Toxicity

4. Repair or Dysrepair

delivery: site of exposure to the target

reaction of the ultimate toxicant with the target molecule

attributes of target

reactivity

accessibility

critical function

outcomes of toxicity

dysfunction

destruction

neoantigen formation

reaction types

noncovalent binding

covalent binding

hydrogen abstration

electron transfer

enzymatic reaction

categories and classification of toxicants

how does a chemical specifically interact with protein targets

activate or inactivate ion channels causing widespread cellular dysfunction and cause cell death and many physiological symptoms

examples

Na+, Ca2+ , K+ levels are extremely important in

-neurotransmission

-muscle contraction

-nearly every cellular function (e.g. tetrodotoxin closes voltage-gated

Na+ channels)

what is the active agent from kraits and what is the MOA

a bungarotoxin

blocks nicotinic AChR

what is the active agent of green mamba snakes and what is the MOA

dendrotoxins blocks K+ channels

what is the active agent of funnel web spiders and what is the MOA

w- agatoxin blocks Ca v 2.1 Ca 2 channels

what is the active agent of coneshell and what is the MOA

w-conotoxin

blocks Cav2.2 Ca channels

what is the active agent of tarantula spiders and what is the MOA

SNX-482

blocks Ca 2.3 Ca channels

what is the active agent of puffer fish and what is the MOA

tetrodotoxin

blocks Na channels

what is the active agent of frog (dendrobates) skin and what is the MOA

alkaloids, batrachotocin, histrionicotoxin

Na channel inhibitor

nicotinic antagonist

alkaloids

group of naturally occuring chemical compounds that mostly contain basic nitrogen atoms

target of alkaloids

voltage gated Na channels

what is the secondary way chemicals can specifically interact with protein targets

inhibit enzymatic processes of bioactive metabolites that alter ion channels and metabolism

Review

what is the first line of defense against nerve gases

•Atropine- mAChR blocker- helps offset ACh excess

•Pralidoxime- reactivation of acetylcholinesterase

what are irreversible anticholinesterase

parathion and sarin

oximes

strong nucleophiles that reactive ACh- esterase