Mechanisms of Toxicity VI

Question 1

Where does oxidative stress come from

Answer 1

arises from an imbalance of pro-oxidants (oxidizing molecular species) and cellular antioxidants

Question 2

What are the two pathways from oxidoreductive stres

Answer 2

Direct (oxidative cell injury) or Indirect (signal transduction gene regulation)
- cells want to remain in reduced state

Question 3

1% of O2 we breathe is reduced to ___

Answer 3

reduced to O2

Question 4

The stepwise reduction of oxygen (O2) leads to the production of _____

Answer 4

Reactive oxygen species (ROS)

Question 5

What are the three things that can happen during ROS

Answer 5

during reactive oxygen species there is
- O2^- which is a superoxide anion radical
- H2O2 which is hydrogen peroxide
- HO Hydroxyl radical
don’t want the hydroxyl radical to be produced, it is the big bad! Most reactive oxygen species, causes double stranded DNA break, half-life is a nano second ie. reacts very fast

Question 6

What are the key points about how xenobiotics become involved in redox cycling and ROS production

Answer 6

1. Reduction xenobiotic donates e- to O2, creating O2^*- super anion radical
2. Amplification: a single xenobiotic can produce many O2^*-
3. Cycling can continue or an extended period cycle continues to spit out O2^-*
   Ie. Paraquat (herbicide)

Question 7

Quinones are readily involved in production of what

Answer 7

ROS

Question 8

NAD(P)H-quinone oxidoreductase (NQO) is induced in response to what?

Answer 8

induced in response to Quinone
- # of enzymes to detoxify

Question 9

glucuronidation

Answer 9

can help to eliminate the OH - OH of a benzene group

Question 10

What other chemical substance is toxicologically relevant ROS

Answer 10

Ozone O3

Question 11

what happens to cause O3

Answer 11

In the presence of ultraviolet light, NO2 derived from motor vehicle exhaust creates oxygen atoms that combine with O2 to produce “ground-level ozone”
- ozone is an extremely reactive ROS with a half-life of 7 minutes, allowing it to move away from motorways to residential areas
can blow through wind causes very toxic effects

Question 12

Oxidoreductive stress causes toxicological damage to…

Answer 12

DNA oxidation
Lipid peroxidation
Protein oxidation
Signaling - apoptosis & gene expression
signaling causing a feedback loop to oxidoreductive stress

Question 13

ROS production can lead to _____
What Factors are there for ROS

Answer 13

Cancer
- however DNA in every cell is attacked by ROS 150,000 times/day, or 10^19 total “hits” per day
- Genetic and environmental factors! Dose Defines the poison

Question 14

Cell signaling and gene regulation by ROS (graph)

Answer 14

Xenobiotics
- ROS/RNA oxidoreductive stress both xenobiotics and this lead to the next step
- Oxidative modification of macromolecules
- Direct Damage
- Redox “sensors”
- Activation of
transcription factors
light switch, tells DNA to do something like turn on mRNA sequence
- Activation of kinases
Both activations lead to
- Gene activation/-inactivation
This leads to three different routes
- Cell proliferation
- Adaptation (induction of stress enzymes, antioxidants)
- Damage

Question 15

What are the four general mechanisms of action

Answer 15

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 increased reactive oxygen species (ROS) leading to oxidative stress - Cornerstone of mechanistic toxicology
4. Bind to receptors (“mimicry”)