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Biology 445/545 – Biology of Toxins
Study Questions
1. Grab your dictionary and look up the definition of "toxic". Is oxygen toxic? Is water? Are
there any substances that aren't toxic? What determines whether something is toxic?
2. Look up the definition of xenobiotic? How is the word relevant to toxicology?
3. Give a good definition of a toxin. Why do organisms produce toxins?
4. What is a venom?
Cell Biology Review (you should be able to answer these from your cell biology background)
5. What is an enzyme? Why are enzymes important to organisms?
6. Describe the basic model of an enzyme-catalyzed reaction. What is the active site? What
is the significance of the “lock-&-key” hypothesis?
7. What do biologists mean by the term “gene expression”? What is involved in the
expression of genes? What is the consequence of gene expression?
8. Give a brief description of the events involved transcription and translation. What
enzyme plays a key role it the process? What is the function of ribosomes?
9. Defend or refute the statement “What a cell is and what it does is dependent on the
proteins it’s synthesizing.”.
10. Draw a cartoon rendition of a plasma membrane. Why is the current model of plasma
membrane structure referred to as the Fluid Mosaic model?
11. Which type of molecule – polar or non-polar – moves through a membrane more readily?
Why is this?
12. What functions do plasma membrane proteins perform?
13. Compare and contrast a cell surface receptor with an enzyme. Why are these receptors
important?
14. Using an appropriate diagram (that you produce), discuss signal transduction in cells.
15. What is the “cytoskeleton”, and why is it important to cells? What can happen if the
cytoskeleton is disrupted?
16. Diagram and describe endocytosis. What role do cell surface receptors play in it?
Principles of Toxicology
17. What is water intoxication? How does it develop, and why is it dangerous? What is
cerebral edema? Discuss Ecstasy in the context of water intoxication and brain
herniation.
18. What was the take-home message from our discussion of water and oxygen toxicity?
***End 1st lecture***
19. What do each of the letters in the acronym ADAME stand for?
20. With respect to toxins, what is meant by the term “absorption”? By the term
“distribution”?
21. Describe the routes of absorption of a toxin. From the perspective of an organism
producing a toxin, discuss the relative strengths/drawbacks of each route. (Hint: you’ll
want to include distribution pathways in your discussion.)
22. What organ system generally plays the key role in distribution of toxins?
23. Present a block diagram of a human’s body fluid compartments, along with some rough
statement about their respective relative volumes (you can use terms like “biggest”,
“smallest”, “lots”, “little”, etc.).
24. Discuss the properties of the barriers that separate the various body fluid compartments,
and speculate about the implications of the barrier’s properties for organisms ‘trying’ to
develop toxins that target specific tissues.
25. What is the primary function of your kidney, and which body fluid compartment does it
work on?
26. For a toxicologist, what is meant by the term “action”? By the term “response”? How do
the two terms relate to one another? What are some examples of responses used by
toxicologists in their study of toxins? Give an example of a plant toxin that produces a
subtle, but potentially serious, response.
27. What are the three factors that determine the response of an organism to a particular
toxin?
28. What is meant by the term “dose”? Contrast administered dose with effective dose.
29. Why do toxicologists use mass-specific doses of a toxin (i.e., mg toxin/kg body mass)
when studying the effects of a toxin?
30. What are the five factors that determine the effective dose of a particular toxin?
31. Discuss exposure pathways and their impact on the effective dose of a toxin. Which
pathways tend to produce the highest effective doses, and why? Which pathways tend to
produce the lowest effective doses, and why?
32. What is meant by the term pharmacokinetics?
33. Construct a diagram that depicts the basic model used by toxicologists to understand
pharmacokinetics of xenobiotics. Use this model to discuss the pharmacokinetics of a
xenobiotic that is administered as
 a single IV bolus
a. What is meant by the term “half-life”? (Google this.)
 a single GI tract bolus
a. What other administration route might be modeled in this way?
 repeated GI tract doses
Be sure to include appropriate graphs in your discussion!
34. What is meant by the terms Area Under the Curve (AUC), and what is its significance to
a budding toxicologist such as yourself?
35. Why are lipophilic toxins often more toxic than more polar, hydrophilic toxins?
36. What is a potential problem for an organism that depends on a toxin that attack
intracellular targets?
***End 2nd lecture***
37. In toxicology, what is meant by the term “response”?
38. Graph the following data and estimate the LD50 for the two toxins:
% of Individuals Showing Response
Dose
( mg/kg )
0
10
Toxin 1
0
0
Toxin 2
0
0
20
30
40
50
60
70
80
2
18
56
83
94
97
99
0
3
96
100
100
100
100
39. In the preceding question, what would you call the NOAEL for Toxin 1? For Toxin 2?
What is he linear range for each of the two toxins?
40. With regard to the toxins used in the preceding question, which toxin would be
considered to be more toxic? Justify your answer.
41. What’s the difference between LD50 and ED50?
42. Suppose you’re a toxicologist working for a pharmaceutical firm, and have been charged
with determining whether a newly-developed chemical would be a good candidate for use
in the treatment of brain cancer. What data would you want in order to make this
assessment, and what experiment(s) would you perform to gather those data? Now, using
an appropriate graph to facilitate your discussion, describe how you would come to a
conclusion about the chemical’s suitability as a chemotherapeutic agent.
43. Use a graph to help you explain what is meant by the toxicological term Margin of
Safety.
44. In terms of therapeutic effect and adverse effects, what must one take into account when
deciding whether a particular drug may be approved for medical use?
45. Describe an experiment whose results indicate the presence of intraspecific ( = within a
species = among the individuals of a species) variation in susceptibility to a toxin. Draw
a graph that illustrates that variation. Can you suggest any explanations for this variation
in susceptibility?
46. Why do the elderly and very young tend to be more susceptible to many toxins?
47. What do biologists mean by the terms ontogeny or ontogenetic? Senescent?
48. Can you suggest any reason(s) why physiological condition can affect susceptibility to
toxins?
49. What do biologist mean when they talk about genetic variation in susceptibility to a
toxin?
50. Use the graph you drew as part of your response to question 40 as part of an explanation
for how resistance to an antibiotic can evolve. Would your explanation apply to other
systems of toxins and the organisms targeted by them?
51. Citing experimental evidence when you can, provide as detailed an answer as you can to
each of the following questions:
 Why do bacteria and fungi produce antibiotics?
 Why don’t all bacteria and fungi produce antibiotics?
 Why aren’t all bacteria resistant to antibiotics?
52. I described an experiment whose results suggested that it was costly for bacteria to
produce and maintain antibiotic resistance mechanisms. Besides the fact that antibiotic
resistance is costly, what other inference can you draw from the results of that
experiment? (Hint: think cost:benefit ratio.)
53. What did the results of the experiment described in the preceding question indicate about
the importance of the environment in the ecology and evolution of organisms?
54. What are the two most prevalent mechanisms of antibiotic action and the three most
frequently observed mechanisms by which bacteria are able to resist the effects of
antibiotics. Do you think these resistance mechanisms are genetically based? Justify
your answer.
55. What is meant by the terms bacteriostatic and bactericidal?
56. Is bacterial resistance to antibiotic action observed outside the hospital or agricultural
setting, i.e., in nature? If so, what does that suggest?
57. Why do meat producers give antibiotic-laced feed to cattle, sheep, and pigs? Can you
suggest any explanations for the observed effect? (note: I didn’t suggest any in lecture)
58. Do you think your answers to question 51 could be generalized to other toxin-producing
organisms? If so, how?
59. Give me two bits of evidence that indicates that toxins are costly for the organisms than
produce them. Give me four examples of possible ecological/evolutionary costs incurred
by an organism that produces a toxin.
60. What is meant by the term inducible? What can we infer when we learn that a system,
such as a toxin, is inducible?
61. The take-home message from our discussion of cost-benefit ratios is…?
***End 3rd lecture***
62. What is meant by the term teratogenic? How did Thalidomide produce its teratogenic
effect?
63. Would you expect there would be a ‘barrier’ between a female mammal’s blood and that
of her developing fetus? Justify your answer. Would you expect this barrier would be
highly permeable, or highly impermeable? Justify your answer.
64. What take-home message(s) do you draw from the comparative data I gave you about the
effects of ethanol, thalidomide, and gasoline in humans and other mammals?
65. What does the term metabolism mean with respect to toxins?
66. Define and discuss biotransformation.
67. What is the primary objective of the body’s metabolic ‘attack’ on toxins, and how is this
objective achieved (3 processes)?
68. In terms of excretion, how does oxidizing a xenobiotic help?
69. What beneficial effect does decreasing lipid solubility have on a toxin? How about
increasing its size?
70. Does biotransformation necessarily render a xenobiotic non-toxic?
71. What is the outcome of Phase I biotransformation? Where in the body does Phase I
biotransformation occur?
72. What is cytochrome P450, what does it do, and why is it important to toxicology?
73. Which phase of biotransformation is P450 involved in?
74. What is the phylogenetic distribution of P450?
75. Describe the evolution of P450s.
76. What is gene fusion?
77. What is gene duplication, and how would it contribute to rapid evolutionary change in a
protein?
78. What environmental ‘events’ seem to have been important in evolution and
diversification of P450s?
79. What evidence do we have that P450s are important in plants? What do plants use them
for?
80. Discuss regulation of P450 levels in cells. What is upregulation? Downregulation?
How do those processes relate to gene expression?
81. Give three implications of the fact that P450s are inducible.
82. Which P450 family is the most diverse in humans? What are some compounds that it
biotransforms?
83. Discuss a downside to CYP2E1 function.
84. Which P450 family is most abundant in humans? In what two organs is it especially
abundant?
85. In terms of drug metabolism, what is the significance of the CYP3A P450 subfamily?
Give some examples of drugs that are biotransformed by it.
86. What do we mean when we say that P450s are non-specific? From a toxicology
standpoint, why is this lack of specificity important?
87. What are some processes that are regulated by histamine, and what is the effect of
histamine on each? How is histamine able to accomplish this regulation?
88. What is meant by the term agonist? Antagonist?
89. What is an antihistamine? What do we use them for?
90. What is a commonly used antihistamine, and what is a downside to its use?
91. How do first-generation antihistamines produce drowsiness?
***End 4th lecture***
92. How do second-generation antihistamines avoid causing drowsiness?
93. Describe in detail the serious problem associated with use of some second-generation
antihistamines such as Allegra. In this context, what is the significance of compounds
such as tricyclic antidepressants, statins and grapefruit juice?
94. What do we mean by the term drug interaction? Using suitable diagrams, describe &
discuss the three main ways they come about.
95. What are the consequences for AUC for the drugs involved in each of the three types of
interaction you just described?
96. How do binding affinities relate to drug interactions?
97. What is the significance for drug interactions of the relative lack of substrate specificity
of P450s? Suggest some hypotheses that might account for that lack of specificity.
98. What is meant by the term genetic polymorphism, and what is its significance for
toxicology?
99. What happens during Phase II of biotransformation, and what is the outcome? Where
does it occur? What are some of the functional groups that play a role in Phase II
biotransformation?
100. Suggest reasons for why biotransformation involves two distinct phases.
101. What is meant by the term bioactivation? Using acetaminophen as an example, discuss
bioactivation and some of its consequences. What is meant by arylation?
102. We said that acetaminophen overdoses now account for the majority of toxic liver failure
cases in the United States. Are these overdoses intentional (suicide, homicide) or
inadvertent? If you believe the latter, how is it possible for inadvertent acetaminophen
overdoses to occur?
103. What is the name of the compound used in emergency treatment of acetaminophen
overdoses, and how does it work?
104. Would acetaminophen overdose be more, or less, of a problem for heavy consumers of
alcohol? Provide a detailed justification for your answer. What evidence is there that
producers of OTC medicines containing acetaminophen believe that alcohol consumption
is associated with an increased risk of acetaminophen-induced hepatotoxicity?
***End 5th lecture***
105. Discuss excretion of toxins. By what avenue are most toxins excreted? What are the
benefit(s) and drawback(s) to this avenue?
106. Describe the excretion of toxins in the bile. Give me one benefit and one drawback to
excreting toxins via the bile. Discuss how the green color of bile is produced. Why can
rh negative babies born to rh positive mothers suffer from jaundice, and what is the term
applied to the condition that produces the jaundice?
107. Tell me as much as you can about milk sickness. How does it occur? What are the
“Trembles”, and how do they relate to milk sickness? Who’s most at risk for developing
it? Who’s least at risk? What role does P450 play in milk sickness?
108. Why is White Snakeroot more toxic in the western and northern parts of its range? What
does that suggest to you? (hint: think cost:benefit from the plant’s perspective)
109. What are cytotoxins?
110. Give the source(s) and mechanism of action for each of the following:
a. Phospholipases, hyaluronidases
b. Hemolysins and leukocidins
c. Sphingomyelinase D
d. Sialidase, neuraminidase
e. Cyanide, cyanogenic compounds
f. Rotenone
g. Hypoglycin A
h. Taxol
111. How does the ability to produce hyaluronidase benefit organisms such as venomous
snakes or bacteria?
112. What is meant by the term “suicide inhibitor”?
113. Why do infections by certain bacteria, such as Group A -hemolytic Streptococcus
pyrogenes, increase our risk of developing autoimmune disease? Hint: you should
include a brief discussion of how our immune system learns to discriminate ‘self’ from
‘non-self’.
114. What is the underlying cause of the high-mortality outbreaks of hypoglycin A poisoning
in its natural habitat, west Africa? I.e., why to the native peoples eat what they know is a
deadly toxic fruit?
115. What is the medical use of taxol, and why is it effective in that application? What are
some of its side-effects, and why do they develop?
***End 6th lecture***
116. What are the commonalities in the way Shigella and certain strains of E. coli attack cells
lining the small intestine? What is different about Shigella once it gains entry to the
cell’s cytoplasm?
117. Compare and contrast the way Salmonella typhi and Shigella dysenteriae attack their
target cells. What are their primary target cells? Why do S. typhi and S. dysenteriae
‘want’ to remain inside their target cells?
118. What is the organism that produces phalloidin and -amanitin, and what is the
mechanism ‘used’ by each toxin? What is unusual about the composition and structure of
the two toxins? How is P450 involved?
119. Describe the A-B mechanism of toxin attack on a target cell. Why is it necessary?
120. Why was diphtheria known as the “White Strangler” and “Strangling Angel of
Children”? (hint: as part of your answer to this question, you should tell me how
diphtheria toxin works.)
121. How does Pseudomonas aeruginosa toxin work?
122. What is a biofilm, and how do bacteria benefit from producing them?
123. Do ricin and abrin use an AB mechanism?
124. How do ricin and abrin cause toxic effects in cells?
125. Chickens are approximately 75x less susceptible to ricin than are mice. What does that
statement mean? Suggest some biochemical or physiological reasons for this. Can you
think of any ecological or evolutionary reasons for the difference in susceptibility?
126. What is phospholipase A2, and what function does it normally perform? How have
venomous snakes adapted the basic molecular structure to make it work for them?
127. What is the target of each of the following types of snake PLA2: cytolytic, myotoxic,
cardiotoxic, hemotoxic?
128. Give a very general summary of the Russell’s Viper story, and tell me what the data
suggest to biologists.
***End 7th lecture***
129. What is the Red Queen Hypothesis, and how is it relevant to the biology of toxins?
130. With respect to the California squirrel-rattlesnake story, suggest possible explanations for
how some squirrel populations are able to be resistant to the snake’s venom.
131. Below is a map showing the NM distribution of a small rodent (the black area) and a
venomous snake that preys on it (the red stippled area). The dark red area shows the zone
of overlap of the two species’ distributions, which is the area where the snake species
actually preys on the rodent.
Design a research project that would test whether coevolution of the snake and prey
has occurred – tell me what kind of data you’d collect, where you’d sample, what
results you’d expect to get from your experiments, etc.
132. What is MAPK, and why is it important to cells?
133. What are oncogenes?
134. Using a suitable diagram, present a detailed discussion of the G-protein signaling
pathway.
135. Why do we say that the G-protein signaling pathway functions like an ON-OFF switch?
What is a benefit of having a signaling pathway that works in this fashion?
136. What is adenyl cyclase, and what does it do?
137. How does pertussis toxin work? What is one of the symptoms of a person who’s infected
by the bacterium that produces pertussis toxin? Why would the bacterium want its victim
to exhibit this symptom?
138. Discuss the three components of anthrax toxin, tell me what each does, and tell me why
the anthrax bacterium would want the three components to do what they do
139. Present a simplified diagram of your gastrointestinal ( = digestive) system, and briefly
describe the function of each part.
140. Take copious notes during an episode of vomiting (yours, or someone else’s), and assess
whether the flow chart I presented in lecture accurately described the sequence of events
you observed.
141. Complete the following table:
Toxin
Source
Mechanism
Effect, Signs &
Symptoms
Interesting Fact I
Learned
Cholera toxin
-----------Okadaic acid
Shiga toxin
-----------Verotoxin
VacA
Cytolethal Distending
Toxin (CdtB)
Saponins
Oxalates (raphides)
142. Using a suitable flow chart (block diagram), discuss information flow through the
nervous system.
143. What is the name of the signal that is used to process information in the nervous system?
144. Diagram and label a typical neuron.
145. Why do we consider a neuron to be an excitable cell? What are some other excitable
cells?
146. What is an action potential? Why is the ability to generate action potentials important?
What do organisms use action potentials for?
147. Use a flow chart as a basis for a discussion of the ion-channel events responsible for the
action potential.
148. How do action potentials spread from point to point along a neuron?
149. Diagram a synapse and use this diagram as the basis for a discussion of transmission of
action potentials across a synapse. Be sure to include the following terms in your
discussion:
 Synaptic bulb
 Synaptic vesicle
 Neurotransmitter
 SNARE complex
 Exocytosis
 Postsynaptic receptor
 AChase
 Gated ion channels
150. With the help of a diagram of a synapse, describe the source, mechanism of action, and
signs/symptoms of poisoning by:
 the –caines
 tetrodotoxin and saxitoxin
 scorpion - and -toxins
 latrotoxin
 botulinum toxin
 nicotine
 - and -bungarotoxin
 curare and succinyl choline
 physostigmine and nerve gases
151. Suppose you’re an emergency room physician, and a patient shows up one day,
complaining of weakness and difficulty breathing, but no pain, fever, or signs of an
infection. Come up with a list of toxins that might explain the symptoms and indicate
exactly why you included each toxin.
152. Now, suppose a patient shows up with severe generalized contractions of his muscles
(i.e., severe seizures). Come up with a list of toxins that might explain the symptoms and
indicate exactly why you included each toxin.
153. What determines whether a given neuron is excitatory or inhibitory? (that’s kind of a
toughie, but the knowledge very important, so be sure you understand the answer)
154. Describe the function of the various parts of the nervous system, including the following
parts of the brain:
 Frontal cortex
 Sensorimotor cortex
 Visual cortex
 Hypothalamus
 Medulla
 Cerebellum
155. What are the two different types of ACh receptors in the nervous system? How do we
identify or detect them? Can you propose a possible explanation for why there are two
different types of ACh receptors?
156. What is excitotoxicity? How does it occur in the CNS?
157. For each of the following neurotransmitters, indicate whether it’s excitatory, inhibitory,
or both in the CNS: ACh, dopamine, GABA, glycine, glutamate/aspartate, and serotonin.
158. What did I mean when I said that the limbic system evolved to reward “fitness-related
behaviors”? Do you think this is significant for our efforts to deal with the problem of
drug addiction?
159. Diagram a dopamine-dependent synapse in your limbic system, and use that as the basis
for discussion of the limbic system’s reward function. What does the limbic system
reward? How does it actually reward us?
160. How does the dopamine-dependent synapse differ from the ACh synapse we talked about
earlier?
161. Compounds that are hallucinogenic usually impact neural pathways in the brain that use
what as their neurotransmitter?
162. Why would I say that pot and chocolate brownies were “made for each other”?
163. How do the various addictive drugs we discussed invoke cravings in users?
164. Using a diagram of a limbic system excitatory dopaminergic synapse, present and discuss
the current model for how addiction can develop, and what happens when one ‘kicks the
habit’.
165. What is the withdrawal syndrome? How does it come about? Why is recovering from
addiction so much more difficult with certain drugs than others?
166. I said that the withdrawal phase of recovering from addiction to ‘stimulants’ (cocaine,
ephedrine derivatives) typically wasn’t as physiologically stressful as withdrawal when
the drug is a CNS depressant such as one of the opiates. Why is that the case?
167. Why is recovering from cocaine or alcohol addiction potentially life-threatening?