Toxicity Mechanisms

Question 1

What are the modifying factors of toxicity?

Answer 1

1. Dose
2. Duration and frequency of exposure
3. Species, strain, individual
4. Gender, pregnancy
5. Age
6. Nutritional status
7. Disease
8. Physical (environmental) factors
9. Social factors

Question 2

what are idiosyncrtic responses/reactions?

Answer 2

toic effects with no known cause; have a genetic component;

Question 3

what are the 4 general mechs of action?

Answer 3

1. Specific localization of xenobiotic (toxicokinetic mechanisms; e.g. tissue binding or active transport)
2. Interference with critical metabolic process (e.g. neurotransmission, ATP production)
3. Bioactivation to electrophiles (e.g. epoxides and reactive oxygen species)
4. Bind to receptors (“mimicry”)

Question 4

Mechanisms of toxicity: toxicokinetics=dose toxicodynamics=response
–toxicodynamics is how the xeno interacts with a target molecule

Answer 4

ya

Question 5

rxn types

Answer 5

noncov binding; cov binding; hydrogen abstraction; electron transfer; enzymatic rxns

Question 6

what is noncov binding?

Answer 6

a. Weak interacions; H-bonds, vdWs
b. Reversible
c. E.g. xenos to plasma protiens, to receptors and enzymes

Question 7

what is cov binding?

Answer 7

a. Very strong, share e’s
b. “irreversible”
c. CYP will make an epoxide, which is a reactive metabolite and the O will covalently bind to DNA nts
d. When enzyme goes to replciate DNA, it won’t be able to because of the epoxide blocking

Question 8

what is hydrogen abstraction?

Answer 8

a. Pulling H off of a molecule

Question 9

what are enzymatic rxns?

Answer 9

a. E.g. snake venoms

b. Can cause proteolytic proteins to activate and break down other proteins

Question 10

what are the main effects on target molecules?

Answer 10

dysfunction or altered function; destruction; or neoantigen formation

Question 11

what is dysfunction or altered function?

Answer 11

○ E.g. dysfunction of DNA molecule due to xeno binding to DNA
○ When xenos interact with receptors may alter function
○ Enzymes involved In critical functions
§ E.g. electron transport chain

Question 12

what is destruction?

Answer 12

○ E.g. suicide inhibition–> destroys the enzyme for good

○ “irreversible” covalent interaction, changes conformation of enzymes so it can no longer work

Question 13

what is neoantigen formation?

Answer 13

“neo” =new, “antigen”–>stimulates Ab response/production
○ Can bind to receptor and stimule Ab response to start killing self-molecules
○ Xenos can be the main problem for autoimmune diseases
Usually indiosyncratic

Question 14

what is the definition of receptors?

Answer 14

Strict definition: Cellular proteins that normally serve as receptors for endogenous ligands (e.g., hormones, neurotransmitters, cytokines)
Broader definition: Enzymes, transport proteins, nucleic acids, structural proteins, membrane lipids (xenobiotic “targets”)

Question 15

structure affects toxicity–affinity of a xeno can be altered by modifying something about it–> isomerizing it; adding another chlorine; may make it 1000x more or less toxic

Answer 15

ya

Question 16

e.g. of isomers of xenobiotics with very different effects

Answer 16

e.g., dextromethorphan (cough suppressant) vs. codeine e.g., stereoisomers of thalidomide

Question 17

what is GPCR?

Answer 17

H--hormone, first messenger
G-proteins--transducers
Effector: AC
cAMP is the second messanger
Activates kinases-->phosphorylates proteins-->activates protein-->amplification
Oer half of all xenos act through GPCRs
--can also change gene transcription

Question 18

what are nuclear receptors?

Answer 18

Nuclear receptor super family
H goes direct into cell, is lipophilic–steroid, thyroid hormones
Affect gene transcription–R might be on the gene to turn on transcription
–ligand activated transcription factors
—has more long-term effects bc it changes proteins and whatnot

Question 19

Tyrosine kinase receptor general info

Answer 19

ATP stimulates TKCR–phosphoryaltes protein
E.g. insulin and growth hormone binds to these receptors
Similar to GCPR (protein phos/act)–through different method

Question 20

ion channel general info

Answer 20

Control mainly Na and Cl’s ability to move in and out of cells
–gates for ions; normally closed; when hormone binds, changes conf, opens, ions rush in–AP generation

Question 21

roles xenos can play with receptors

Answer 21

agonist, antagonist, partial agonist; endocrine disruptors

Question 22

what are agonists?

Answer 22

○ Binds to receptor and mimics endogenous ligand

Produces a full response

Question 23

What are antagonistic xenos?

Answer 23

○ Binds to receptor but produce no response
§ Blockers–beta blockers
Competitive (binds to receptor) or noncomp (binds to site other than receptor–changes conformation?)

Question 24

what are partially agonistic xenos?

Answer 24

○ Binds to receptor but produces a lesser response
○ Based on the affinity for the partial agonist for the receptor
○ Agonist is like a light switch–>turn it on, lights up–>partial ag. I like a dimmer switch–>less of a response

Question 25

what are endocrine disruptive xenos?

Answer 25

○ Xenos can interfere with endocrine system and function in us
○ Act as partial ags
Most are able to mimic steroid hormones, lipophilic, can interact with nuclear receptors, alter gene expression

Question 26

what is receptor theory?

Answer 26

• [xeno]+[receptor] determines [XR] which determines the effect

Question 27

receptor subtypes

Answer 27

• Adrenergic receptors–endogenous ligand is NE
○ Have both alpha (1,2) and beta (1,2) subtypes
§ Subtypes of subtypes

Question 28

what are alpha 1 receptor subtypes?

Answer 28

§ A1 adrenergic receptors are highly expressed on arterioles–main vasculature which control vasodilation and constriction
When NE binds, causes cells to contract and control BP

Question 29

what are beta 2 receptor subtypes?

Answer 29

§ B2 present in bronchioles
□ Smooth muscle cells (same in artioles) contain lots of B2
□ When an NE bidns to a B2, you get relaxation of smooth muscle cells, allowing bronchioles to open
□ Used in asthma–have constriction in bronchioles

Question 30

what are orphan receptors?

Answer 30

• Receptors with no known endogenous ligand
• Opiates
• Morphine binds to opioid receptors (also have subtypes)
○ Fetanyl is 100 times more potent than morphine–means it binds to 100 times more tightly to receptors–will have 100 times the effect
• E.g. cannabinoid receptors
○ Bind THC (tetrahydracannabinol??)
○ Don’t know what the endogenous ligand is–we have endogenous ligands in our brain which produce a similar effect to THC
§ may be involved in hunger
• E.g. aryl hydrocarbon receptor (AhC)

Question 31

symptoms of OP poisoning

Answer 31

SLUDS– ○ Salivation, lacrimation, urination, defecation
○ OPs stimulate GI tract (defecation), fluid release
Most responses are due to overstim of muscarinic receptors (parasym receptor)

Question 32

OP overdose treatment

Answer 32

• Can use atropine as a treament
○ Antagonist of muscarinic receptor (blocker)
From belladonna alkaloids–used to be taken to dilate pupil
• Pralidoxine (2-PAM)
○ OPs Bind to ACh-esterase–inactivate
○ 2-PAM Reactivates enzyme –pulls OP off of enzyme
• Benzodiazepene (BDZ)
○ OP poisoning leads to excitement/anxiety–BDZ relaxes them