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| Prof PK Gupta Founder Society of Toxicology of India |
PK Gupta Series 15: Toxicology
Mechanism of Action-Question and Answers, (MCQs)
The book "Illustrated
Toxicology" is
an essential, practical resource for self-study and guidance catering to a
broad spectrum of students. This book (published by Elsevier, USA 1sr Ed 2018 covering 640 pages) covers a range of core toxicological
areas, including pesticides, radioactive materials and poisonous plants, also
presenting a section on veterinary toxicology. Across 16 chapters, the book
presents key concepts with the aid of over 250 detailed, full-color
illustrations. Each section is supplemented with practical exercises to support
active learning. This combination of clear illustrations and sample testing
will help readers gain a deeper understanding of toxicology.
This
book is useful for toxicology, pharmacy, medical and veterinary students, and
also serves as a refresher for academics and professionals in the field,
including clinical pharmacists, forensic toxicologists, environmentalists and
veterinarians.
Q. Define mechanism of toxicity?
Mechanism
of toxicity is the study of how chemical or physical agents interact with
living organisms to cause toxicity. Knowledge of the mechanism of toxicity of a
substance enhances the ability to prevent toxicity and design more desirable
chemicals; it constitutes the basis for therapy upon overexposure, and
frequently enables a further understanding of fundamental biological processes.
Q. Describe
mechanism of action?
Term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect
toxic response. A mechanism of action usually includes mention of the specific molecular
targets to which the drug binds, such as an enzyme or receptor. Receptor
sites have specific affinities for drugs based on the chemical structure of the
drug, as well as the specific action that occurs there. Drugs that do not bind
to receptors produce their corresponding therapeutic effect by simply interacting
with chemical or physical properties in the body. Common examples of drugs that
work in this way are antacids and laxatives.
Mode of Action
Q. What are different
types of mode of toxic actions?
There are two major types of modes of toxic
action.
b)
Specific: specific acting toxicants are those that are
non-narcotic and that produce a specific action at a specific target site.
Q. What is non-specific type of mode of action?
Non-specific acting
modes of toxic action result in narcosis;
therefore, narcosis is a mode of toxic action. Narcosis is defined as a
generalized depression in biological activity due to the presence of toxicant molecules in the organism. The target site
and mechanism of toxic action through which narcosis affects organisms are
still unclear, but there are hypotheses that support that it occurs through alterations in the cell
membranes at specific sites of the membranes, such as the lipid
layers or the proteins bound to the
membranes. Even though continuous exposure to a narcotic toxicant can produce death, if the exposure to the toxicant is stopped, narcosis
can be reversible.
Q.
What do you mean by specific type of mode of actions?
Toxicants that at low concentrations modify or inhibit some biological process by binding at a
specific site or molecule have a specific
acting mode of toxic action. However,
at high enough concentrations, toxicants with specific acting modes of toxic
actions can produce narcosis that may or may
not be reversible. Nevertheless, the specific action of the toxicant is always
shown first because it requires lower concentrations.
Q. What are different specific modes of toxic actions?
·
Uncouplers of oxidative phosphorylation: The action
involves toxicants that uncouple the two processes that occur in oxidative phosphorylation: electron
transfer and adenosine
triphosphate (ATP) production.
·
Acetylcholinesterase (AChE)
inhibitors: AChE is an enzyme associated with nerve synapses that it’s designed to regulate nerve impulses by breaking
down the neurotransmitter Acetylcholine (ACh). When toxicants bind to AChE, they inhibit the
breakdown of ACh. This results in continued nerve impulses across the synapses,
which eventually cause nerve system damage. Examples of AChE inhibitors are organophosphates and carbamates, which are components found in pesticides (seeAcetylcholinesterase inhibitors).
·
Irritants. These are
chemicals that cause an inflammatory effect on living tissue by chemical action at the site of
contact. The resulting effect of irritants is an increase in the volume of cells due to a change in size (hypertrophy) or an increase in the number of cells (hyperplasia). Examples of irritants are benzaldehyde, acrolein, zinc sulphate and chlorine.
·
Central nervous system (CNS)
seizure agents. CNS seizure agents inhibit cellular
signaling by acting as receptor
antagonists. They result in the inhibition of
biological responses. Examples of CNS seizure agents are organochlorine pesticides.
·
Respiratory blockers. These
are toxicants that affect respiration by interfering with the electron
transport chain in the mitochondria. Examples of respiratory blockers are rotenone and cyanide.
Mechanism of Toxicity
Q. What are the steps involved in the
process of mechanisms of toxicity?
Ø Delivery: Site of Exposure to the Target
Ø Reaction
of the Ultimate Toxicant with the Target Molecule
Ø Cellular Dysfunction and Resultant Toxicity
Ø Repair
or Dysrepair (Fig 1)
nature.berkeley.edu/~dnomura/pdf/Lecture6Mechanisms3.pdf
Q.
What are the chemical factors that cause cellular dysfunction?
Ø Chemicals
that cause DNA adducts can lead to DNA mutations which can activate cell death
pathways; if mutations activate oncogenes or inactivate tumor suppressors, it
can lead to uncontrolled cell proliferation and cancer (e.g. benzopyrene)
Ø Chemicals
that cause protein adducts can lead to protein dysfunction which can activate
cell death pathways; protein adducts can also lead to autoimmunity; if protein
adducts activate onco genes or inactivate tumor suppressors, it can lead to
uncontrolled cell proliferation and cancer (e.g. diclofenac glucuronidation
metabolite)
Ø Chemicals
that cause oxidative stress can oxidize DNA or proteins leading to DNA
mutations or protein dysfunction and all of the above. (e.g. benzene, CCl4)
Ø Chemicals
that specifically interact with protein targets chemicals that activate or
inactivate ion channels can cause widespread cellular dysfunction and cause
cell death and many physiological symptoms—Na+, Ca2+, K+ levels are extremely
important in neurotransmission, muscle contraction, and nearly every cellular
function (e.g. tetrodotoxin closes voltage-gated Na+ channels)
Ø Chemicals
that inhibit cellular respiration—inhibitors of proteins or enzymes involved in
oxygen consumption, fuel utilization, and ATP production will cause energy
depletion and cell death (e.g. cyanide inhibits cytochrome c oxidase)
Ø Chemicals
that inhibit the production of cellular building blocks, e.g. nucleotides,
lipids, amino acids (e.g. amanitin from
Deathcap mushrooms) that alter ion channels and metabolism (e.g. sarin inhibits
acetylcholinesterase and elevates acetylcholine levels to active signaling
pathways and ion channels)
All
of the above can also cause inflammation which can lead to cellular dysfunction
Q.
What are two forms of cell deaths?
A. Necrosis: unprogramed
cell death (dangerous)
a) Passive form of cell
death induced by accidental damage of tissue and does not involve activation of
any specific cellular program.
b). Early
loss of plasma membrane integrity and swelling of the cell body followed by
bursting of cell.
c). Mitochondria
and various cellular processes contain substances that can be damaging to
surrounding cells and are released upon bursting and cause inflammation.
d). Cells necrotize in
response to tissue damage [injury by chemicals and viruses, infection, cancer,
inflammation, ischemia (death due to blockage of blood to tissue) (Fig. 2 )
Fig 2: Extensive tissue necrosis of the dorsum of hand
B. Apoptosis: one
of the main forms of programmed cell death (not as dangerous to organism as
necrosis).
a). Active form of cell death enabling individual
cells to commit suicide.
b). Caspase-dependent
c). Dying
cells shrink and condense and then fragment, releasing small membrane-bound
apoptotic bodies, which are phagocytosed by immune cells (i.e. macrophages).
d). Intracellular
constituents are not released where they might have deleterious effects on
neighbouring cells.
Q.
What is necrosis of tissues?
Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or
trauma which result in the unregulated digestion of cell components. Cell commits homicide is necrosis (Fig 2)
Q.
What is apoptosis?
Apoptosis is the term used to describe the
generally normal death of the cell in living organisms. Since new cells
regenerate, cell death is a normal and constant process in the body.
Q. What are the different stages of apoptosis?
Apoptosis has several distinct stages. In the
first stage, the cell starts to become round as a result of the protein in the
cell being eaten by enzymes that become
active. Next, the DNA in the nucleus starts to come apart and shrink down. The
membrane surrounding the nucleus begins to degrade and ultimately no longer
forms the usual layer (Fig 3.3). Cell commits suicide by apoptosis.
Fig 3: Different steps involved
during the process of necrosis and apoptosis
Q. Differentiate necrosis and apoptosis.
The following table highlights
major differences between necrosis and apoptosis
Table : Difference
between necrosis and apoptosis
NECROSIS
|
APOPTOSIS
|
v Cellular
swelling
v Membranes are
broken
v Cell lysis,
eliciting an inflammatory reaction
v DNA
fragmentation is random, pyknosia
v Mechanism—ATP
depletion, membrane injury, free radical damage
v In vivo,
whole areas of the tissue are affected
|
v Cell
shrinkage
v Membranes
remain intact
v Cell is
phagocytosed, no tissue reaction
v DNA
fragmentation in to nucleosome size fragments
v Mechanism-caspase
activation, endonuclease and ptoteases
v In vivo,
individual cells appear affected
|
Question and Answer
Exercises
Q.1. What are the possible toxic mechanisms for chemicals?
- Produce
reversible or irreversible bodily injury;
- Have the
capacity to cause tumors, neoplastic effects, or cancer;
- Cause
reproductive errors including mutations and teratogenic effects;
- Produce
irritation and sensitization of mucous membranes;
- Cause a
reduction in motivation, mental alertness, or capability;
- Alter
behavior or cause death of the organism.
Q.2. List the variety of processes of absorption
including their characteristics.
i.
Diffusion:
molecules move from areas of high concentration to low concentration;
ii.
Facilitated
Diffusion: require specialized carrier proteins, no high energy phosphate bonds
are required;
iii.
Active
Transport: ATP is required in conjunction with special carrier proteins to move
molecules through a membrane against a concentration gradient.
iv.
Endocytosis:
particles and large molecules that might otherwise be restricted from crossing
a plasma membrane can be brought in or removed by this process.
Q.3. How do toxic substances enter the body?
There are several ways in which toxic substances can
enter the body. They may enter through the lungs by inhalation, through the
skin, mucous membranes or eyes by absorption, or through the gastrointestinal
tract by ingestion.
Q.4. What are the major functions of the skin?
The skin can help to:
- regulate
body temperature through sweat glands;
- provide a
physical barrier to dehydration, microbial invasion, and some chemical
insults;
- excrete
salts, water, and organic compounds;
- serve as a
sensory organ for touch, temperature, pressure and pain;
- provide
some important components of immunity.
Q.5. What are the three major mechanisms for the harmful
effects of environmental toxins?
- The toxins
influence on enzymes;
- Direct
chemical combination of the toxin with a cell constituent;
- Secondary
action as a result of the toxins presence in the system.
Q.6. List the four major types of hypersensitivity
reactions:
- cytotoxic;
- cell-mediated;
- Immune
complex;
- Anaphylactic.
Q. 7 What is the difference between mode of action and
mechanism of toxicity?
A mode of action should not be confused
with mechanism of action, which refers to
the biochemical processes underlying a given mode of action. Modes of
toxic action are important, widely used tools in
ecotoxicology and aquatic toxicology because they
classify toxicants or pollutants according to their type of
toxic action.
Q.8 Define mode of toxic action?
A mode of
toxic action is a common set
of physiological and behavioral signs that characterize a type
of adverse biological response.
Q. 9 What is cytotoxicity
Cytotoxicity is the quality of being toxic to cells. Treating cells with the cytotoxic compound
can result in a variety of cell fates. The cells may undergo necrosis, in which they lose membrane integrity and die
rapidly as a result of cell
lysis. The cells can stop
actively growing and dividing (a decrease in cell viability), or the cells can
activate a genetic program of controlled cell death (apoptosis). Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (Bitis arietans) or brown recluse spider (Loxosceles reclusa).
Q. 10 What is anaphylaxis?
Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. It typically causes more than one of the following: an
itchy rash, throat or tongue swelling, shortness of breath, vomiting, lightheaded ness, and low blood pressure. These
symptoms typically come on over minutes to hours. Common causes include insect bites and stings, foods, and medications.
Multiple choice questions
Exercise
2
Q.1
A possible reason for the selective embryofetal toxicity of DES is --.
a)
higher concentration of free DES in embryo / fetal compared to adults
b)
binding to retinoic acid receptors
c)lack
of placental drug metabolism
d)all
of the above
Q.2.
the liver and kidney are major target organs of toxicity because------.
a) they both receive a high percentage of
cardiac output.
b)
they both have substantial xenobiotic metabolizing capacity
c)
they both have transport systems that can concentrate xenobiotics
d)
all of the above
Q.3.
acyl glucuronides are particularly toxic to the liver because ---.
a)
they selectively interact with macrophages releasing active oxygen.
b)
active transport systems in the hepatocyte and bile duct system can greatly up concentrate
them.
c)
they are resistant to glucuronidase
d)
they are suitable inhibitors of UGT2B7
Q.4.
the selective renal toxicity of cephaloridine over cephalothin is due to -----
a)
selective uptake by the organic cation transporter
b)
selective inhibition of P-glycoprotein
c)
selective uptake by the organic anion transporter
d)
significantly less plasma protein binding of cephaloridine
Q.3.
all of the following are of alpha-amanitin except ....
a) it is less orally available than phalloidin.
b)
it inhibits RNA polymerase II.
c)
it is transported into the hepatocyte by a bile acid transporter.
d)
it is a mushroom toxin
Q.6.
all of the following are true of the toxic mechanism of paraquat except ---.
a)
lungs accumulate paraquat in an energy dependent manner
b)
its energy into the lungs is assumed to be via the polyamine transport system.
c)
similar molecules with smaller distances between nitrogen atoms do not enter
lungs as readily.
d) cytotoxicity to alveolar cells is caused by
interference with calcium channels.
Q.7. enzyme induction of phenobarbital is mediated
through -
a)
aryl hydrocarbon receptor
b)
PPAR- alpha receptor
c) constitutively active receptor (CAR)
d)
estrogen receptor
Q.8.
CAR is down regulated by -----
a)
hypericum extracts
b)
acetaminophen
c)aspirin
d)
proinflammatory cytokines
Q.9.
the pregnane X receptor ----
a)
is a cytosolic receptor
b)
is involved in induction of CYP3A4
c)
is primarily expressed in skin
d)all
of the above
Q.10.
xenobiotic toxicity that occurs after repair and adaptive processes are over helmed
include all of the following except -.
a)
fibrosis
b)
apoptosis
c)
necrosis
d)carcinogenesis
Answers
1.a; 2.
d ; 3.b ; 4.c ; 3.a ; 6.d ; 7.c
; 8.d ; 9.b ; 10. b.
Further Reading
Gupta PK (2016) Fundamentals of
Toxicology: Essential concepts and applications. 1st
Edition. ISBN-9780128054260, pp 438, BSP/Elsevier, USA
Gupta PK
(2018) Illustrative Toxicology with Question bank. 1st
Edition. Elsevier, USA pp 640
https://www.elsevier.com/books/illustrated-toxicology/gupta/978-0-12-813213-5
Gupta PK (2018) Toxicology: Resource
for Self-Study Questions: Ist Ed pp
Published by All Solutions You Need:
www. http://allsolutionsyouneed.blogspot.com,
Kinder direct publications: Amazon.com
https://www.amazon.com/TOXICOLOGY-Resource-Self-Study...ebook/.../B07DDFW...
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