2 mechanisms of toxicity I

Question 1

what is the graph of an overview of mechanisms of toxicity?

Answer 1

Question 2

why is it important to understand toxic mechanisms?

Answer 2

Question 3

understanding mechanisms of toxicity informs _________________

Answer 3

risk assessment
1. do we have a problem with this xeno (detect)
2 and 3. dose and response (exposure=kinetics) (mechanism=dynamics)
4. what we think is safe conc of xeno (risk assessment)

Question 4

what are the four general mechanisms of toxic action?

Answer 4

1. specific localization of xeno (toxicokinetic mechanisms; ex: tissue binding or active transport)
2. interfere with critical metabolic process (ex: neurotransmission (organophosphate compounds), ATP production (cyanide and CO))
3. bioactivation to electrophiles (ex: epoxides) and increased reactive oxygen species leading to oxidative stress
4. bind to receptors (mimicry) (ex: lead mimics calcium)

Question 5

what are the four steps involved in toxicity in a graph?

Answer 5

Question 6

what is the toxicology paradigm?

Answer 6

Question 7

what is step one?

Answer 7

delivery (ADME)

Question 8

what is step 2a?

Answer 8

interactions with a target molecule

Question 9

what are the four attributes of target molecules in 2a?

Answer 9

interaction of ultimate toxicant with target molecule
1. proteins (enzymes, receptors, structural proteins, carriers (Hb), cofactors (GSH)
2. nucleic acid (DNA, RNA) (most carcinogenic)
3. lipids (cell membranes)
4. Carbohydrates (glucose but millions so not a toxic effect)

Question 10

what are the 5 major reaction types in 2a?

Answer 10

1. noncovalent binding
2. covalent binding
3. hydrogen abstraction
4. electron transfer
5. enzymatic reactions

Question 11

what is noncovalent binding?

Answer 11

-recall: hydrogen and ionic bonding, van der waals forces, hydrophobic interactions (weaker)
-most common reaction and reversible
-ex: receptors binding, plasma protein binding (ex; albumin affinities)

Question 12

what is covalent binding?

Answer 12

-very toxicologically relevant
-irreversible damage to molecule (unless repaired)
-recall: electrophiles (free radicals and epoxides)
-when two chemicals share electrons and very strong chemical bond
-glutathione provides electron for radical hydroxide

Question 13

what is hydrogen abstractions?

Answer 13

-free radicals can abstract (pull) hydrogen atom off a molecule
-forms a new radical

Question 14

what is electron transfer (redox reactions)?

Answer 14

-ex: nitrites can oxidize Fe2+ to Fe3+ in hemoglobin, producing methemoglobinemia (unable to carry oxygen)

Question 15

what are enzymatic reactions?

Answer 15

-ex: proteolytic snake and spider venoms break down protein (proteinlysis)

Question 16

what are effects on target molecules (outcomes)?

Answer 16

1. dysfunction
2. destruction
3. neoantigen formation

Question 17

what is dysfunction?

Answer 17

-most common effects
-usually inactivates or inhibits target molecule (ex: receptors, enzymes, electron transfer chain, hemoglobin)

Question 18

what is destruction?

Answer 18

-destroys or kills target molecule
-ex: damage to membrane lipids (lipid peroxidation) of cells
-ex: grapefruit juice kills CYP3A4, (“suicide inhibitors” of CYP3A4), permanent and irreversible, enzyme will never work again

Question 19

what is neoantigen formation?

Answer 19

-rare; idiosyncratic (genetically based, unexplained)
-new antigen which stimulates an immune response
-ex: toxicant-induced autoimmune diseases such as lupus

Question 20

what is step 2b?

Answer 20

alteration of the biological microenvironment
-effects are not initiated by reactions with target molecules
-ex: precipitation of ethylene glycol (antifreeze, tastes sweet) in kidney tubules to produce oxalic acid crystals (causes extreme pain, kidney failure and death) causes physical disturbance
-ex: non-polar solvents and detergents that alter membrane lipid fluidity and disrupt ion gradients (mechanism of action of ethanol, disrupts ion homeostasis)

Question 21

what is the summary of steps 1 and 2?

Answer 21