Molecular Toxicology Exam 3

Electrophiles

Molecules with an area of low-electron density

Normally the xenobiotic

Often detoxified by non-sensitive nucleophiles

Nucleophiles

Molecules with an area of high-electron density

Normally the biological molecule

Factors that promote/determine covalent binding to proteins

Reactivity of metabolite and distance to target

High concentrations of reactive metabolite

Availability of defense mechanisms

How do microcystins result in toxicity via covalent binding?

Produced by Cyanobacteria, has an electrophilllic center, hepa-toxins

Taken up into the hepatocytes by a multispecific organic anion transporter, binds to protein phosphate and causes hyperphosphorilation of the cytoskeleton that doesn’t allow it to rebuild itself

Toxicity of organophosphate pesticides

Toxicity determined by P=O group and potent acute toxicity

Binds to Esteric site and causes build up, can’t depolarize/repolarize

PCBs And how they affect thyroid hormone levels

Polychlorinated Biphenyls disrupt thyroxin homeostasis with enlarged thyroid glands and decreased T4

How do tetrodotoxin affect sodium in cells?

TTX blocks voltage gated Na+ channels like a plug and causes build up

Resting potential is unchanged and no action potential is propagated

How does saxitoxin affect sodium in cells?

Binds and blocks voltage gated Na+ channels when closed and causes build up

Can’t depolarize membrane, blocks neuron activity and affects peripheral nervous system

How does pyrethroids affect sodium in cells?

Binds to open voltage gated Na+ channels and lets Na+ keep flowing in

Can’t repolarize membrane

What are the two toxicologically important families of nuclear receptors?

Steroid hormone receptors

PAS receptor

Steroid hormone receptor

Form dimers

Ligand binding domain and DNA binding domain

Ex: Estrogen receptor

PAS receptors

Form heterodimers

Ligand binding domain, dimerization domain, and DNA binding domain

Ex: AhR

Describe the different domains of nuclear receptors

Ligand binding domain- Where ligands bind at

Dimerization domain - Binds to specific protein (ARNT on PAS receptors)

DNA binding domain - Binds to DNA

Activation of AhR pathway

Ligand binds to AhR in cytoplasm and HSP90 unbinds, enters the nucleus and dimerizes to form a heterodimer with ARNT, binds to XREs and activates AhRR which produces negative feedback and CYP1A1 that turns on phase I metabolites

AhRR competes with AhR for ARNT and XRE; unbound AhR goes back to the cytoplasm

What is the relationship between to AhR and toxicity?

Bond strength and turn on many pathways

How does TCDD elicit toxicity?

Induces oxidative stress through SH groups, intracellular Ca, production of ROS, and oxidation of DNA

AhR is the determinant factor in the mice study where removing CYP1A did not affect the downstream pathway

Describe the toxicity of compounds that bind to the estrogen receptor

Bind to a range of ligands other than estrogen (ones with aromatic ring and phenol), phase I metabolites bind to it

Low risk due to low concentration, affinity for receptors and species specific roles

How does DDE elicit toxicity? Mechanisms?

Blocks expression of testosterone pathway

Induces CYP450 aromatase

Displace testosterone from binding site on AR

Binds to AR in unstable configuration

What factors of the immune system are important for immune-mediated toxicity?

Decentralized system

Innate and modern systems

Modulate immune function at different levels

How is immune toxicity caused through innate immune cells?

Enhance tissue injury

How is immune toxicity caused through the modern immune system?

Immunosuppression

Immunostimulatory effects

Immunosuppression

Suppression of the maturation and development of immune cells

Immunostimulatory effects

Enhancing of function of immune system that result in harmful reaction

Hapten recognition - Immune system attacks hapten

Conformational change of protein - Immune system attacks hidden peptide

Immune system modulation - Immune system attacks peptide since cell is registered as a non-self cell

Autoimmune reactions

Autoreactive T cells don’t recognize self vs non-self and attack peptide/itself

Drug and metabolite increase autoreactive T cell production

Immunoallergy

Immune response activated by toxin and T cell/antibody attacks haptenated peptide

What are idiosyncratic reactions?

Rare adverse reactions based on a specific combination of factors within an individual

What are organophosphate pesticides?

Used as pesticides, lipophilic compounds readily absorbed through the skin and distributed

Consequences of organophosphate pesticides

Bronchonstriction, muscle weakness, psychological disorders

Treatment for organophosphate pesticides

Atropin (blocks receptors from binding)

Oximes (dephosphorylates AChE)

Phosphorothionates (reduce toxicity to mammals)

Altered mechanism for organophosphate pesticide

Organophosphate binds to Esteric site instead of acetylcholine and causes a build up of acetylcholine

Mechanism for organophosphate

Acetyl CoA and Choline bind to create Acetylcholine and enter a vesicle to be transported to the end of the axon terminal. Once a nerve impulse happens, the acetylcholine is released into the gap junction to be received by cholinergic receptor or AChE where it binds to the Serine site and and breaks down into choline and acetate