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Biology 402/502 – 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. What is a xenobiotic?
3. Give a good definition of a toxin. Why do organisms produce toxins?
4. What is a venom?
Cell Biology Review
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”?
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. Draw a cartoon rendition of a plasma membrane. Why is the current model of plasma membrane
structure referred to as the Fluid Mosaic model?
10. Which type of molecule – polar or non-polar – moves through a membrane more readily? Why is
this?
11. What functions do plasma membrane proteins perform?
12. Compare and contrast a cell surface receptor with an enzyme. Why are these receptors important?
13. Using an appropriate diagram (that you produce), discuss signal transduction in cells.
14. What is the “cytoskeleton”, and why is it important to cells? What can happen if the cytoskeleton
is disrupted?
15. Diagram and describe endocytosis. What role do cell surface receptors play in it?
Principles of Toxicology
16. 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.
17. What do each of the letters in the acronym ADAME stand for?
18. With respect to toxins, what is meant by the term “absorption”? By the term “distribution”?
19. 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.)
20. What organ system generally plays the key role in distribution of toxins?
21. 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.).
22. 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.
***End 1st Lecture***
23. What is the primary function of your kidney, and which body fluid compartment does it work on?
24. For a toxicologist, what is meant by the term “action”? By the term “response”? How do the two
terms relate to one another? Give an example of a plant toxin that produces a subtle, but
potentially serious, response.
25. What are the three factors that determine the response of an organism to a particular toxin?
26. What is meant by the term “dose”? Contrast administered dose with effective dose.
27. What are the five factors that determine the effective dose of a particular toxin?
28. 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?
29. What is meant by the term pharmacokinetics?
30. Construct a diagram that depicts the basic model we use 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”?
 a single GI tract bolus
a. What other administration route can be modeled in this way?
 repeated GI tract doses
Be sure to include appropriate graphs in your discussion!
31. What is meant by the terms Area Under the Curve (AUC), and what is its significance to a
budding toxicologist such as yourself?
32. Why are lipophilic toxins often more toxic than more polar, hydrophilic toxins?
33. What is a potential problem for an organism that depends on a toxin that attack intracellular
targets?
34. In toxicology, what is meant by the term “response”?
35. Graph the following data and estimate the LD50 for the two toxins:
% of Individuals Showing Response
Dose
( mg/kg )
0
10
20
30
40
50
60
70
80
Toxin 1
0
0
2
18
56
83
94
97
99
Toxin 2
0
0
0
3
96
100
100
100
100
36. 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?
37. With regard to the toxins used in the preceding question, which toxin would be considered to be
more toxic? Justify your answer.
38. What’s the difference between LD50 and ED50?
39. 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.
nd
***End 2 Lecture***
40. Use a graph to help you explain what is meant by the toxicological term Margin of Safety.
41. 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?
42. 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?
43. Why do the elderly and very young tend to be more susceptible to many toxins?
44. What do biologists mean by the terms ontogeny or ontogenetic? Senescent?
45. Can you suggest any reason(s) why physiological condition can affect susceptibility to toxins?
46. What do biologist mean when they talk about genetic variation in susceptibility to a toxin?
47. 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?
48. 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?
49. 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.)
50. What are the two most prevalent mechanisms of antibiotic action? 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.
51. What is meant by the terms bacteriostatic and bactericidal?
52. Is bacterial resistance to antibiotic action observed outside the hospital or agricultural setting, i.e.,
in nature? If so, what does that suggest to you?
53. Why do we 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)
54. Do you think your answers to questions 46 and 48 could be generalized to other toxin-producing
organisms? If so, how?
55. 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.
56. What is meant by the term inducible? What can we infer when we learn that a system, such as a
toxin, is inducible?
57. What is meant by the term teratogenic? How did Thalidomide produce its teratogenic effect?
58. 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.
59. 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?
rd
***End 3 Lecture***
60. What does the term metabolism mean with respect to toxins?
61. Define and discuss biotransformation.
62. What is the primary objective of the body’s metabolic ‘attack’ on toxins, and how is this objective
achieved (3 processes)?
63. In terms of excretion, how does oxidizing a xenobiotic ***help***?
64. What beneficial effect does decreasing lipid solubility have on a toxin? How about increasing its
size?
65. Does biotransformation necessarily render a xenobiotic non-toxic?
66. What is the outcome of Phase I biotransformation? Where in the body does Phase I
biotransformation occur?
67.
68.
69.
70.
71.
72.
73.
What is cytochrome P450, what does it do, and why is it important to toxicology?
Which phase of biotransformation is P450 involved in?
What is the phylogenetic distribution of P450?
Describe the evolution of P450s.
What is gene fusion?
What is gene duplication, and how would it contribute to rapid evolutionary change in a protein?
What environmental ‘events’ seem to have been important in evolution and diversification of
P450s?
74. What evidence do we have that P450s are important in plants? What do plants use them for?
75. Discuss regulation of P450 levels in cells. What is upregulation? Downregulation? How do
those processes relate to gene expression?
76. Give three implications of the fact that P450s are inducible.
77. Which P450 family is the most diverse in humans? What are some compounds that it
biotransforms?
78. Discuss a downside to CYP2E1 function.
79. Which P450 family is most abundant in humans? In what two organs is it especially abundant?
80. In terms of drug metabolism, what is the significance of the CYP3A P450 subfamily? Give some
examples of drugs that are biotransformed by it.
81. What do we mean when we say that P450s are non-specific? From a toxicology standpoint, why
is this lack of specificity important?
82. 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?
83. What is meant by the term agonist? Antagonist?
84. What is an antihistamine? What do we use them for?
85. What is a commonly used antihistamine, and what is a downside to its use?
86. How do first-generation antihistamines produce drowsiness?
87. How do second-generation antihistamines avoid causing drowsiness?
88. Describe in detail the serious problem associated with use of some second-generation
antihistamines such as Allegra. What is the significance of compounds such as tricyclic
antidepressants, statins and grapefruit juice?
th
***End 4 Lecture***
89. What do we mean by the term drug interaction? Using suitable diagrams, describe & discuss the
three main ways they come about.
90. What are the consequences for AUC for the drugs involved in each of the three types of
interaction you just described?
91. How do binding affinities relate to drug interactions?
92. 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.
93. What is meant by the term genetic polymorphism, and what is its significance for toxicology?
94.
95. 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?
96. Suggest reasons for why biotransformation involves two distinct phases.
97. What is meant by the term bioactivation? Using acetaminophen as an example, discuss
bioactivation and some of its consequences. What is meant by arylation?
98. 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?
99. What is the name of the compound used in emergency treatment of acetaminophen overdoses, and
how does it work?
100. 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?
101. Discuss excretion of toxins. By what avenue are most toxins excreted? What are the benefit(s)
and drawback(s) to this avenue?
102. Describe the excretion of toxins in the bile. Give me one benefit and one drawback to excreting
toxins via the bile.
103. 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?
***End 5th Lecture***