Lecture 5: Cellular and Tissue Targets of Toxicity Flashcards
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.
true
what are the four steps of the mechanisms of toxicity?
- delivery
- interaction with target (or microenvironment)
- progression to cellular dysfunction
- inappropriate repair (or adaptation) at any point
what is the first step of the mechanisms of toxicity?
delivery
absorption, distribution toward target, reabsorption, and toxication are all examples of things that…
increase delivery to target
presystemic elimination, distribution away from target, excretion, detoxication are all examples of…
factors that decrease delivery to target
______: Biotransformation that
increases toxicity (aka metabolic activation)
Toxication
______: Biotransformation
that prevents the formation of a toxic metabolite or eliminates it once formed
detoxication
what is the second step in mechanisms of toxicity?
interaction with target molecule(s)
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 ____
toxicants on target molecules
T/F: toxicants can target a molecules AND/OR the microenvironment
true!
what are some examples of ways a toxicant can alter the biological microenvironment… causing toxicity
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
T/F: Alterations in gene expression can result from exposure to toxicants
true!
If a toxicant has high affinity to certain cellular receptors it may…
Directly alter expression of certain genes through activating transcription factors
ex: estrogenic compounds binding to estrogen receptors
If a toxicant binds to certain types of membrane receptors it may…
Activate a cell signaling pathway(s) that can lead to altered gene expression
T/F: Some toxicants can cause oxidative stress
true!
reactive oxygen species (ROS)
what are the three main types of reactive oxygen species?
superoxide (O2)
hydroxyl radical (HO)
hydrogen peroxide (H2O2)
where do we accidentally make ROS?
in the mitochondria
what four enzymes can remove superoxide radicals?
superoxide dismutase (SOD),
glutathione peroxidase (GPX),
peroxiredoxin (PRX), and catalase (CAT)
why do we not need an enzyme to eliminate HO?
has an extremely short half-life, no need!
T/F: Some toxicants cause dysregulation of cell function
true
Basically, binding to and altering the function of a target molecule, pretty much everything ever lol
Aerobic metabolism mainly occurs in the ________ (i.e.,TCA cycle and
oxidative phosphorylation) to make ATP
(in the presence of oxygen)
mitochondria
With oxidative phosphorylation, the ________ used in this process
are transferred to oxygen in a controlled
way to form water.
high energy electrons
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 _______)
homeostasis
______ = the tendency toward a relatively stable equilibrium
Homeostasis
what are the three critical ways a toxicant can disrupt cell function?
ATP depletion
Sustained rise in intracellular Ca2+
Overproduction of ROS (and RNS)
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?
the cell cannot carry out normal functions
what can increased cytosolic Ca2+ do to the cell?
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
T/F: Cells maintain a 10,000-fold difference in concentration of
Ca2+ between the exterior of
the cell and the cytosol
true!
T/F: Inside the cell, there’s a large difference between Ca2+ levels in the endoplasmic
reticulum (high) and the
cytosol (low)
true!
T/F: xenobiotics can directly produce ROS/RNS
true!
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 ________
ROS and RNS
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.
- The cell partially compensates by pumping Ca2+ into the mitochondria, which
decreases the H+ separation across the mitochondrial membrane hindering ATP
synthase. - 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. - ROS and RNS can further reduce ATP reserves as the cell tries to detoxify them.
- 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.
cell function (death spiral)
When does a cell go through
necrosis vs. apoptosis?
main determinant is extent of mitochondrial damage
second determinant is whether DNA is damaged or not
what kicks off necrosis, as shown by cell culture studies?
depletion of ATP
what is apoptosis?
programmed and orderly cell death- a natural process!
T/F: In moderate levels of
mitochondrial damage,
membranes and organelles get broken down and engulfed by phagocytes
true
how is apoptosis often triggered?
by cytochrome C leaking from mitochondria (since its involved in oxidative phosphorylation)
once the cytochrome C signal is received, the ‘executioner’ _______ signals to
begin the apoptosis process
caspases
______ – cell
death when damage cannot be repaired
necrosis
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
mitochondrial permeability transition
(MPT)
when an MTP occurs, what happens?
all aerobic ATP production stops
excess of free radicals released into cytosol
cell membrane becomes permeable
cell swells and bursts
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 ______
repairs
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 _____
adaptation
what are three examples of toxicity resulting from inappropriate repair and adaptation?
tissue necrosis
fibrosis
carcinogenesis
cancer is caused by…
uncontrolled cell division
There are genes that normally signal the cell to progress through the cell cycle (called ____ if their altered regulation causes cancer)
oncogenes
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 _______)
tumor suppressor genes
which step of cancer is irreversible
when it enters the progression stage, when there’s proliferation of cells… WIL lead to cancer
Mutagens can be carcinogens through altering DNA by what two ways?
- 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) - 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
T/F: not all mutagens ‘hit’ important cancer-causing genes
true! not all mutagens are carconigens!
Carcinogens can also be _____ that directly kill cells or speed up their division
toxicants
what are the two main forms of carcinogens that can also be toxicants?
- carcinogens that cause high cell death
- hormones that mimic signals for cell division when it should not
both these examples lead to a higher probability of gaining a mutation
asbestos is a carcinogen but NOT a _____
mutagen
just causes lots of cell death… COULD lead to chance of mutation
