PK Gupta Series 13: Toxicology MCQ and Fill in the Blanks

PK Gupta Series 13: Toxicology  MCQ and Fill in the Blanks

Exercise 

Q. 1. All of the following are hydrolytic enzymes except---------

a) carboxylesterase

b) alcohol dehydrogenase

c) cholinesterase

d) paraoxonase

Q. 2. All of the following are true of epoxide hydrolyases except------------

a) they add oxygen to a double bond and form a 3-member ring

b) they are important in hydrolyzing electrophiles

c) they play a role in converting benzo(a)pyrene to a carcinogen

d) some forms are inducible

Q. 3. Nitroreductase plays an important role in ----------

a) nasal epithelium

b) lung Clara cells

c) white blood cells

d) intestinal flora

Q. 2. A drug that undergoes sulfoxide reduction is --

a) haloperidol

b) chloramphenicol

c) thaliomide

d) sulindac

Q. 5. Quinidine oxidoreductases are thought to play a protective role in -------

a) liver toxicity of microcystin

b) bone marrow toxicity of benzene

c) renal toxicity of aminoglycosides

d) neurotoxicity of n-hexane

Q. 6. All of the following are mechanisms for removing halogen atoms aliphatic xenobiotics except ---------------------

a) Grignard dehalogenation

b)reductive dehalogenation

c)oxidative dehalogenation

d)double dehalogenation

Q. 7. Oxidation of ethanol to acetaldehyde takes place in-

a) cytosol

b) microsomes

c) peroxisomes

d) all of the above

Q. 8. Reductive dehalogenation of carbon tetrachloride produces -------

a) phosgene

b) chloroform

c) trichloromethyl radical

d) hydrochloric acid

Q. 9. Acetaldehyde is converted to acetic acie by ALDH2 in ---------------

a) mitichondria

b) cytosol

c) microsomes

d)all of the above

Q. 10. Aldehyde oxidase and xanthene oxidoreductase contain -----------

a) zinc

b) molebdenum

c) selenium

d) copper

Answers

1.       b; 2. a; 3. d; 2. d; 5. b; 6.a ; 7.d; 8. c; 9. a; 10. b .

Exercise

Q. 1. Slow acetylators of NAT demonstrate all of the following except--------

a) peripheral neuropathy from isoniazid

b) systemic lupus erythematous from procainamide

c) peripheral neuropathy from dapsone

d) decreased hypotensive response from hydrazine

Q. 2. In contrast to glucuronidation, sulfonation is ----

a) a low-affinity, low-capacity pathway

b) a low-affinity, high-capacity pathway

c) a high-affinity, high-capacity pathway

d) a high-affinity, low-capacity pathway

Q. 3. Induction of sulfotransference enzymes by rifampin be clinically relevant for -----------

a) warfarin

b) digoxin

c) ethinyl estradiol

d) all of the above

Q. 2. All of the following statements regarding sulfonation reaction are true except -------

a) they can take a molecule less lipid soluble

b) they always detoxify a molecule

c) some drugs must be metabolized to a sulfonate conjugate to have pharmacologic effect

d) morphine-6-sulfate is more potent than morphine in the rat

Q. 5. All of the following statements are true regarding methylation except-------------

a) the process generally decreases the water solubility of the parent

b) the process can mask functional groups that can be metabolized by other conjugation enzymes

c) inorganic mercury and arsenic can be dimethylated

d) high methyltransferace activity may lower levels of homocysteine

Q. 6. All of the following are methyltransferase enzymes except --------------

a) SAM

b) COMT

c)NNMT

d) HNMT

Q. 7. All of the following are true of glucuronide conjugates of xenobiotics except ---------------

a) they can excreted in the urine

b)thaey are formed from activated xenobiotics

c) they are substances for beta-glucuronidase in the intestinal flora

d) they can excreted into bile

Q. 8. All of the following are true of sulfonation reaction except -----------

a) they involve the transfer of sulfate

b) they are catalyzed by sulfotransferaces

c) the cofactor of the reaction is PAPS

d) they are mainly excreted in the urine

Q. 9. The number of UGT mammalian enzymes that have been identified is approximately ---

a) 5

b)12

c)22

d) 58

Q. 10. In addition to cytoplasm, sulfotranferaces are present in mammals in the -------------

a) endoplasmic reticulum

b) mitochondria

c) plasma membrane

d)Golgi apparatus

Answers

1.       d; 2. d; 3. c; 2. b; 5.d ; 6. a; 7, b; 8. a; 9.c; 10.  d.

Fill in the blanks

Exercise

Q. 1. The most common process of absorption of xenobiotics across the cell membrane is -------------------.

Q. 2. The important route of excretion for xenobiotics is ---------------------.

Q. 3. The process of chemical transformation (conversion from one form to another) occurring in the body is known as----------------------------.

Q. 2. The major site for biotransformation of xenobiotics in body is---------------.

Q. 5. In a hepatocyte, metabolism of xenobiotics takes place in-----------------------------------------------------------------------------.                              .

Q. 6. The most important among microsomal enzymes is --------------------or------------------------------------------.

Q. 7. The major biotransformation reaction occurring in Phase I is ------------------and in Phase II is -------------------.

Q. 8. Phase I Oxidation reactions are mainly catalyzed by -----------------------------------------.

Q. 9. All Phase II conjugation reactions are catalysed by non- microsomal enzymes except for ------------------------------------ which is catalysed by microsomal enzymes.

Q. 10. The ability of certain substances to increase the activity or synthesis of microsomal enzymes is known as ------------------------------.

Q. 11. The metabolic reaction, which is deficient in dogs is---------------------; Cats are deficient in ---------------------------------------and Pigs are deficient in ------------------- reactions of biotransformation.

Q. 12. The process of conversion of nontoxic substance into a toxic metabolite due to biotransformation is known as --------------------------------.

Answers

1. Passive diffusion; 2. RENAL EXCRETION; 3. BIOTRANSFORMATION; 2. LIVER(Liver is the major site due to the presence of variety of metabolizing enzymes. Other important sites for biotransformation include lung, kidney and intestines); 5. ENDOPLASMIC RETICULUMN (ER) or MICROSOMES.; 6. MONOOXYGENASES or MIXED FUNCTION OXIDASES (MFO); 7. OXIDATION and  CONJUGATION; 8. MICROSOMAL ENZYMES (MFO); 9. GLUCURONIDE  CONJUGATION; 10. INDUCTION (Non-microsomal enzymes which are present in cytosol are not inducible) –microsomal enzymes which are present in cytosol are not inducible); 11. ACETYLATION; GLUCURONIDE CONJUGATION and SULFATION; (Hence, sulphonamides which undergo acetylation cause toxicity in dogs and similarly, paracetamol, which undergoes glucuronide conjugation, causes hepatotoxicity in cats). 12. LETHAL SYNTHESIS.

True and False Statements

Exercise 

True and False statement. Write T for true and F for false statement.

Q.1. A water-soluble drug will pass across muscle membranes faster than across brain membranes (assume permeability-rate limitations).

Q.2.A neutral, lipophilic drug is likely to be absorbed faster in the intestines than in the stomach. Remember that stomach and intestine differ in their properties.

Q.3.Lipophilic drugs are generally taken up fast by highly perfused organs.

Q.2.Ionized and lipophilic drugs are most likely to cross most membrane barriers.

Q.5.Drugs with a high tissue binding always have a large volume of distribution.

Q.6.Compared to skin, liver would have a higher rate of uptake of perfusion-limited lipophilic drugs due to its higher blood flow rate.

Q.7.Distribution to a specific tissue for permeability-limited hydrophilic drugs depends on how much and how quickly the blood gets to the specific tissue.

Q.8.Perfusion limited distribution is a type of drug distribution into tissue that occurs when the drug is able to cross membranes easily.

Q.9. Assume two drugs (identical molecular weight, same dose given): one neutral drug (Drug A) and one acidic drug (pka=7.4, Drug B). Drug A and the unionized form of drug B have the same partition coefficient. The fraction unbound in plasma and tissue is 0.5 for both drugs. Drug B will enter tissues somewhat slower than drug A.

Q.10. A weak acid, whose unionized form shows a high partition coefficient is likely to cross most membrane barriers.

Answers

1.T; 2.T; 3.T; 2.F; 5. F; 6.T; 7. F; 8. T;  9.T;10.T

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PK Gupta Series 15: Toxicology (Mechanism of Action) Question and Answers, (MCQs),

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.

a)       Non-specific: non-specific acting toxicants are those that produce narcosis.

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)

 

Fig 1: Mechanisms of Toxicity

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

https://openi.nlm.nih.gov/imgs/512/94/2740528/PMC2740528_IJPS-41-145-g001.png?keywords=necroses

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

https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiC0fz2Vx7rzGVofwyjjCGzTF6dc66enilOD273GcHyr9Lhx9ZdqcGaNXr8y2Y5Xskdb7vEUmBgPjp7hixcymUG4ToJEsFHuqfumZGeWgVRq_KNM8IeTa5RKNIe0e0JKHIvBuy2YUspq6E/s1600/Necrosis+Vs+Apoptosis.pnge

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?

1. Produce reversible or irreversible bodily injury;
2. Have the capacity to cause tumors, neoplastic effects, or cancer;
3. Cause reproductive errors including mutations and teratogenic effects;
4. Produce irritation and sensitization of mucous membranes;
5. Cause a reduction in motivation, mental alertness, or capability;
6. 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:

1. regulate body temperature through sweat glands;
2. provide a physical barrier to dehydration, microbial invasion, and some chemical insults;
3. excrete salts, water, and organic compounds;
4. serve as a sensory organ for touch, temperature, pressure and pain;
5. provide some important components of immunity.

Q.5. What are the three major mechanisms for the harmful effects of environmental toxins?

1. The toxins influence on enzymes;
2. Direct chemical combination of the toxin with a cell constituent;
3. Secondary action as a result of the toxins presence in the system.

Q.6. List the four major types of hypersensitivity reactions:

1. cytotoxic;
2. cell-mediated;
3. Immune complex;
4. 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 https://www.elsevier.com/books/fundamentals-of-toxicology/.../978-0-12-805426-0

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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