2 mechanisms of toxicity VI

Question 1

oxidative stress arises from ____________

Answer 1

an imbalance of pro-oxidants (oxidizing molecular species) and cellular antioxidants (protection against)

Question 2

what is the outline of this lecture (xenobiotic-induced oxidative stress)?

Answer 2

1. introduction to reactive oxygen species (ROS)
2. mechanisms of ROS production
3. toxicological outcomes of oxidative stress
4. antioxidant defense mechanisms
5. intracellular signaling and gene regulation by oxidative stress

Question 3

what is oxidative stress?

Answer 3

-we will mainly look at the direct oxidative cell injury (DNA, lipids and proteins)
-we have cells which cause oxidative burst to kill of infections
-ageing=accumulative oxidative stress

Question 4

how often are radicals produced?

Answer 4

1% of O2 we breathe is reduced to O2-
-the stepwise reduction of oxygen (O2) leads to the production of reactive oxygen species (ROS)
-H2O2 can cause double strand DNA breaks
-HO has half life of a few nano seconds

Question 5

what is a simple example of how xenobiotics become involved in redox cycling and ROS production?

Answer 5

key points
1. reduced xeno donate e- to O2, creating O2-
2. amplification: a single xeno can produce many O2-
3. cycling can continue for an extended period of time (until gets metabolized and excreted in the body)

Question 6

what is the example of a quinone?

Answer 6

quinone (xenobiotic)= always an aromatic ring, two ketone groups
-quinones are readily involved in ROS production
-similar to acetaminophen
-gets excreted by sulfonation or glucuronidation
-benzene targets bone marrow (causes leukemia)

Question 7

what is another very important toxicologically relevant ROS?

Answer 7

ozone (O3)
-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
-high levels of ozone are produced in very urbanized areas, where high smog (from vehicles)

Question 8

what are the toxicological outcomes of oxidative stress? what are the ROS involved?

Answer 8

Question 9

ROS production can lead to __________

Answer 9

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!
-dont want it to affect the genome (want apoptosis and necrosis to avoid mutations)

Question 10

what is the cell signaling and gene regulation by ROS?

Answer 10

-redox sensors (ex: mitochondria)
-transcription factors: either produce or not mRNA production (can turn on for antioxidants, GST)
-kinases activated by being phosphorylated (adding of a phosphate group)
-gene activation/inactivation= increased or decreased mRNA production

Question 11

what is the review of the four general mechanisms of action (whole module)?

Answer 11

1. specific localization of xenos (toxicokinetic mechanisms ex:tissue binding or active transport)
2. interference with critical metabolic process (ex: neurotransmission, ATP production)
3. bioactivation to electrophiles (ex: epoxides) and increased reactive oxygen species (ROS) leading to oxidative stress
4. bind to receptors (“mimicry”): how xenos can mimic endogenous xeno and cause adverse effects (but also beneficial because a lot of drugs are made to mimic natural things in the body)
   -endocrine disruptors are xenos that mimic endogenous hormones (ex; estrogen)