Lecture 5: Cellular and Tissue Targets of Toxicity

Question 1

T/F: A toxicant interacts with a tissue or cell to result in a toxic effect. The
adverse effect only happens if the toxicant is at a sufficient
concentration at the cellular target.

Answer 1

true

Question 2

what are the four steps of the mechanisms of toxicity?

Answer 2

1. delivery
2. interaction with target (or microenvironment)
3. progression to cellular dysfunction
4. inappropriate repair (or adaptation) at any point

Question 3

what is the first step of the mechanisms of toxicity?

Answer 3

delivery

Question 4

absorption, distribution toward target, reabsorption, and toxication are all examples of things that…

Answer 4

increase delivery to target

Question 5

presystemic elimination, distribution away from target, excretion, detoxication are all examples of…

Answer 5

factors that decrease delivery to target

Question 6

______: Biotransformation that
increases toxicity (aka metabolic activation)

Answer 6

Toxication

Question 7

______: Biotransformation
that prevents the formation of a toxic metabolite or eliminates it once formed

Answer 7

detoxication

Question 8

what is the second step in mechanisms of toxicity?

Answer 8

interaction with target molecule(s)

Question 9

Dysfunction of target molecules
(i.e., activation or inhibition of protein target molecule)

Destruction of target molecules
(e.g., cleavage of the phosphodiester bond of DNA)

Neoantigen (new antigen) formation due to DNA damage and mutations

…are all examples of the effects of ____

Answer 9

toxicants on target molecules

Question 10

T/F: toxicants can target a molecules AND/OR the microenvironment

Answer 10

true!

Question 11

what are some examples of ways a toxicant can alter the biological microenvironment… causing toxicity

Answer 11

Alteration of cell membrane and destruction of essential solute gradients

Some toxicants alter H+ ion concentrations which disrupts the acid-base balance

Toxicant causes harm by occupying a site or space

Question 12

T/F: Alterations in gene expression can result from exposure to toxicants

Answer 12

true!

Question 13

If a toxicant has high affinity to certain cellular receptors it may…

Answer 13

Directly alter expression of certain genes through activating transcription factors

ex: estrogenic compounds binding to estrogen receptors

Question 14

If a toxicant binds to certain types of membrane receptors it may…

Answer 14

Activate a cell signaling pathway(s) that can lead to altered gene expression

Question 15

T/F: Some toxicants can cause oxidative stress

Answer 15

true!
reactive oxygen species (ROS)

Question 16

what are the three main types of reactive oxygen species?

Answer 16

superoxide (O2)
hydroxyl radical (HO)
hydrogen peroxide (H2O2)

Question 17

where do we accidentally make ROS?

Answer 17

in the mitochondria

Question 18

what four enzymes can remove superoxide radicals?

Answer 18

superoxide dismutase (SOD),
glutathione peroxidase (GPX),
peroxiredoxin (PRX), and catalase (CAT)

Question 19

why do we not need an enzyme to eliminate HO?

Answer 19

has an extremely short half-life, no need!

Question 20

T/F: Some toxicants cause dysregulation of cell function

Answer 20

true
Basically, binding to and altering the function of a target molecule, pretty much everything ever lol

Question 21

Aerobic metabolism mainly occurs in the ________ (i.e.,TCA cycle and
oxidative phosphorylation) to make ATP
(in the presence of oxygen)

Answer 21

mitochondria

Question 22

With oxidative phosphorylation, the ________ used in this process
are transferred to oxygen in a controlled
way to form water.

Answer 22

high energy electrons

Question 23

Some of the ATP produced is used to drive ion pumps that keep the concentrations of ions in the cell within
specific ranges (part of _______)

Answer 23

homeostasis

Question 24

______ = the tendency toward a relatively stable equilibrium

Answer 24

Homeostasis

Question 25

what are the three critical ways a toxicant can disrupt cell function?

Answer 25

ATP depletion Sustained rise in intracellular Ca2+ Overproduction of ROS (and RNS)

Question 26

A toxicant that interferes with any step of aerobic metabolism will decrease the overall levels of ATP in the cell... without enough ATP, what happens?

Answer 26

the cell cannot carry out normal functions

Question 27

what can increased cytosolic Ca2+ do to the cell?

Answer 27

Cause increased pumping of Ca2+ into the mitochondria, both depleting ATP and decreasing ATP synthesis. Disrupt the cytoskeleton, which requires low [Ca2+ ] for stability. This can cause membrane instability. Certain hydrolytic enzymes are activated by Ca2+ These can then start to break down integral membrane proteins and membrane lipids

Question 28

T/F: Cells maintain a 10,000-fold difference in concentration of Ca2+ between the exterior of the cell and the cytosol

Answer 28

true!

Question 29

T/F: Inside the cell, there’s a large difference between Ca2+ levels in the endoplasmic reticulum (high) and the cytosol (low)

Answer 29

true!

Question 30

T/F: xenobiotics can directly produce ROS/RNS

Answer 30

true!

Question 31

High Ca2+ levels in the mitochondria activate the TCA cycle, causing more electrons to flow through the electron transport chain to ATP synthase. If ATP synthase is inhibited, electrons can mistakenly get transferred to oxygen or nitrogen, forming ________

Answer 31

ROS and RNS

Question 32

loss of ____________: 1. Depletion of cellular ATP deprives the endoplasmic reticulum and plasma membrane Ca2+ pumps of “fuel”, causing rise of Ca2+ in the cytoplasm. 2. The cell partially compensates by pumping Ca2+ into the mitochondria, which decreases the H+ separation across the mitochondrial membrane hindering ATP synthase. 3. Hindering ATP synthase causes the formation of free radicals, which can impact the Ca2+ pumps that normally pump Ca2+ outside the cell, further contributing to high levels of Ca2+ in the cytoplasm. 4. ROS and RNS can further reduce ATP reserves as the cell tries to detoxify them. 5. The ROS and RNS species can directly damage membranes, causing leakage of ions out of the cell, and the leakage of Ca2+ from the outside to the inside of the cell.

Answer 32

cell function (death spiral)

Question 33

When does a cell go through necrosis vs. apoptosis?

Answer 33

main determinant is extent of mitochondrial damage second determinant is whether DNA is damaged or not

Question 34

what kicks off necrosis, as shown by cell culture studies?

Answer 34

depletion of ATP

Question 35

what is apoptosis?

Answer 35

programmed and orderly cell death- a natural process!

Question 36

T/F: In moderate levels of mitochondrial damage, membranes and organelles get broken down and engulfed by phagocytes

Answer 36

true

Question 37

how is apoptosis often triggered?

Answer 37

by cytochrome C leaking from mitochondria (since its involved in oxidative phosphorylation)

Question 38

once the cytochrome C signal is received, the ‘executioner’ _______ signals to begin the apoptosis process

Answer 38

caspases

Question 39

______ – cell death when damage cannot be repaired

Answer 39

necrosis

Question 40

during necrosis, a ______ occurs, an abrupt increase in inner mitochondrial membrane permeability leads to opening a pore and the contents leak out into the cytosol

Answer 40

mitochondrial permeability transition (MPT)

Question 41

when an MTP occurs, what happens?

Answer 41

all aerobic ATP production stops excess of free radicals released into cytosol cell membrane becomes permeable cell swells and bursts

Question 42

Molecular repair of proteins, lipids, and DNA * Reversal of chemical alterations * Removal of damaged unit and replacement with newly synthesized unit Cellular repair * Autophagic removal of damaged cell organelles * Clearance and regeneration of damaged axons Tissue repair * Deletion of injured cells and regeneration of the tissue by proliferation ...these are all examples of mechanisms of ______

Answer 42

repairs

Question 43

Decreasing delivery to the target * Decreased absorption * Increased sequestration by intracellular binding proteins * Enhanced detoxification * Cellular export Decreasing the target density or responsiveness * Receptor downregulation Increasing Repair * For example, the induction of chaperones to repair misfolded proteins ...these are all examples of mechanisms of _____

Answer 43

adaptation

Question 44

what are three examples of toxicity resulting from inappropriate repair and adaptation?

Answer 44

tissue necrosis fibrosis carcinogenesis

Question 45

cancer is caused by...

Answer 45

uncontrolled cell division

Question 46

There are genes that normally signal the cell to progress through the cell cycle (called ____ if their altered regulation causes cancer)

Answer 46

oncogenes

Question 47

There are genes that normally signal the cell to not progress through the cell cycle, or signal DNA repair, or apoptosis when there is irreparable DNA damage (called _______)

Answer 47

tumor suppressor genes

Question 48

which step of cancer is irreversible

Answer 48

when it enters the progression stage, when there's proliferation of cells... WIL lead to cancer

Question 49

Mutagens can be carcinogens through altering DNA by what two ways?

Answer 49

1. Binding to DNA as adducts. The cell repairs these by a mechanism that isn’t perfect, and a different nucleotide base can be accidentally inserted causing a change in the DNA code (i.e., mutation) 2. Directly damaging the DNA. ROS and radiation can do this. Repairing damaged DNA is error-prone and can cause a change in the DNA sequence

Question 50

T/F: not all mutagens ‘hit’ important cancer-causing genes

Answer 50

true! not all mutagens are carconigens!

Question 51

Carcinogens can also be _____ that directly kill cells or speed up their division

Answer 51

toxicants

Question 52

what are the two main forms of carcinogens that can also be toxicants?

Answer 52

1. carcinogens that cause high cell death 2. hormones that mimic signals for cell division when it should not both these examples lead to a higher probability of gaining a mutation

Question 53

asbestos is a carcinogen but NOT a _____

Answer 53

mutagen just causes lots of cell death... COULD lead to chance of mutation