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Bimm118 Worksheet #3 (REVISED)
TA: John Diep
1. What generally happens to a drug in Phase I reactions?
Drug is usually converted into a more hydrophilic metabolite by adding or unmasking functional groups.
2. List some examples of Cytochrome P450 enzyme inducers and inhibitors.
Barbiturates – induces CYP2B
Ethanol – induces CYP2E
Cigarette smoke/Charred foods – induces CYP1
Grapefruit juice – inhibits CYP3A4
Ketoconazole (antifungal) – inhibits CYP3A4
3. Explain the mechanism behind the “cheese reaction”.
Tyramine (in old cheese) is structurally similar to norepinephrine and is metabolized by peripheral MAO
(monoamine oxidase).
1. MAOi (monoamine oxidase inhibitor) causes an accumulation of tyramine and increased absorption
from the GI into the blood
2. High levels of tyramine will displace norepinephrine (NE) from storage vesicles
3. Displaced NE will trigger a sympathetic response and cause a hypertensive crisis
Note: MAOi also inhibits the metabolism of the displaced NE
4. What are the two major Phase II conjugation reactions? Which reaction occurs at high
substrate concentration?
Glucuronidation and Sulfation. Predominantly glucuronidation at high substrate concentrations.
5. Name the functional groups that are susceptible to the addition of glucuronic acid.
Carboxyl group, alcohols/phenols, amines, amides, and sulfonamides
6. Glucuronidation products are often excreted with the bile. Define enterohepatic recycling.
When the glucoronic acid conjugated drug is excreted with the bile into the GI, it may be subjected to
glucoronidases (produced by microbial flora) that will cleave the bond, releasing the drug from glucoronic acid. The
free drug can then be reabsorbed.
7. When acetaminophen is metabolized by P450 enzymes, a toxic metabolite is produced.
Which Phase II conjugation reaction is involved in the detoxification of this metabolite?
Glutathione Conjugation.
8. Alcohol induces a P450 enzyme involved in the metabolism of acetaminophen. How does
alcohol consumption with acetaminophen increase the risk of hepatotoxicity?
Increased levels of the P450 enzyme will accelerate the production of the toxic metabolite in the liver. Glutathione
will eventually be depleted and the accumulation of the toxic metabolite will cause liver toxicity.
9. The effect from activating a kinase-linked receptor and a nuclear receptor usually persists
even after the ligand is removed. Explain.
Kinase-Linked Receptors and Nuclear Receptors usually trigger a cellular response by modifying transcriptional
activity and affecting protein synthesis. So the cellular effect is not dependent on the ligand (after receptor
activation), but rather on the proteins that persist after the ligand is gone.
10. What makes Calcium an effective second messenger (in terms of its cellular
concentrations)?
Cytosolic Ca2+ is very low (100nM)
-steep ion gradient allows for rapid diffusion of Ca2+ across membranes
-small changes in Ca2+ permeability can have a prominent effect
These properties make Ca2+ an ideal second messenger because signal transduction will be very rapid due to the
steep ion gradient and very sensitive because only a small Ca2+ influx into the cytosol will dramatically change the
Ca2+ concentration there.
11. Describe verapamil’s action on Ca2+ channels, its specificity, and the physiological
response.
Verapamil inhibits both L and T Type calcium channels. Blocking L-Type calcium channels causes vasodilation
since they are primarily distributed in the vascular smooth muscles, which helps to lower blood pressure. Blocking
T-Type calcium channels, which are primarily found in the conductile fiberes of the heart, will reduce heart rate.
The latter effect is undesirable in patients who already have a weak/impaired heart.
12. Digoxin, a digitalis alkaloid, can be used to treat congestive heart failure. Explain the drug’s
mechanism of action.
Digoxin is a Na+/K+ ATPase inhibitor. It reduces the Na + concentration gradient that Na+/Ca2+ Exchanger relies on
to pump Ca2+ out of the cell. Increased cytosolic Ca2+ in the contractile cardiac fibers (due to decreased efficiency
of the Na+/Ca2+ Exchanger) allows for stronger contractions in the heart.
13. How does cholera toxin affect the cell signaling pathway? How does pertussis toxin differ?
Cholera Toxin
-ribosylation of Gαs ;
-this inhibits release of GTP, so it stays active
-constant stimulation of adenylate cyclase (AC),
-AC catalyzes ATP  cAMP
-cAMP increases GI secretions
-results in fluid/electrolyte loss and severe diarrhea
Pertussis Toxin
-ribosylation of Gαi;
-this inhibits the release of GDP, so it stays inactive
-because it’s inactive, there’s no inhibition of AC
-cAMP levels increases; causing the whooping cough
14. What two drugs mentioned in class elevates cGMP levels? Briefly describe how these drugs
raise cGMP levels.
Sildenafil (Viagra) – Phosphodiesterase V inhibitor. Blocks the breakdown of cGMP to GMP.
Nitroglycerin – converted into Nitric Oxide (NO). Nitric oxide activates guanylyl cyclase. Guanylyl cyclase
catalyzes GTP  cGMP