CYP Enzymes (basic)

Question 1

Why would one name CYP3A4 in that manner?

Answer 1

3 = family (>40% sequence-homology)
A = subfamily (>55% sequence-homology)
4 = isoenzyme!!

Question 2

Where are most of the cytochrome p450’s found and bound?

Answer 2

Mostly LIVER, also in lung, kidney, heart, brain;

lipid membranes of SER

Question 3

Define prodrug, induction, inhibition, polymorphism, substrate:

Answer 3

Prodrug: med administered in inactive or less than fully active form, then converted to active form
Induction: Biotrans by induced CYP enzymes leading to increased prodrug activity or enhanced drug elimination
Inhibition: increased bioavailability of drug or decreased prodrug activity
Polymorphism: genetic change existing for ONE percent of population (enzyme can be altered with biotransforming properties altered)
Substrate: substance acted on by enzyme

Question 4

Substrate, inhibitor, inducer(s) for 1A2?

Answer 4

Substrate: caffeine, theophyllin (asthma)
Inhibitor: grapefruit juice
Inducer: smoking, charred food

Question 5

Substrate, inhibitor(s) and inducer(s) for 2C9?

Answer 5

Substrate: phenytoin, S-warfarin
Inhibitor: macrolides
Inducer: St John’s wort

Question 6

Substrate, inhibitor(s), inducer for 2c19?

Answer 6

Substrate: Diazepam (valium)
Inhibitor: fluoxetine (depression)
Inducer: St John’s wort

Question 7

Substrate, inhibitor, inducer(s) for 2D6

Answer 7

Substrate: codeine
Inhibitor: quinidine (anti-malaria), haloperidol (anti-psychotic)
Inducer: rifampin

Question 8

Substrate for 2E1?

Answer 8

Substrate: Paracetamol (tylenol/acetaminophen)

Question 9

Substrate, inhibitor(s), and inducer(s) for 3A4?

Answer 9

Substrate: terfenadine (anti-his), verapamil (anti-hypertensive and vasculature)
Inhibitor: ketoconazole, itraconazole (both antifungals)
Inducer: St. John’s wort

Question 10

Which three enzymes have polymorphisms?

Answer 10

2C9, 2C19, 2D6

Question 11

Which three enzymes could lead to poor metabolism because of polymorphisms? Which enzyme could lead to extensive metabolism?

Answer 11

2C9, 2C19, 2D6; 2D6

Question 12

Who are you looking at as potentially being poor metabolizers?

Answer 12

Asian (15-20%), AA (20%), white (3-5%) for 2C19; more minimal in 2C9

Question 13

If an Ethiopian/Spanish soldier comes in with some pain. What are you worried about giving?

Answer 13

Polymorphisms in 2D6 affecting 30% Ethiopians, 10% Southern Europeans that could metabolize the codeine into morphine too quickly –> opioid toxidrome (sedative)

Question 14

Where is Cyp2D6 located? What types of mutations lead to no activity, decreased, or increased activity?

Answer 14

Chr 22; no activity: splicing or frameshift;

decreased: missense;
increased: copy number variant

Question 15

What does thiopurine methyltransferase normally do? Consequence of TPMT mutations?

Answer 15

Catalyzes s-methylation and inactivates the 6-MP used for immunosuppression and leukemia treatment;
defect in TPMT will accumulate high levels of 6-MP which can lead to bone marrow failure

Question 16

Who would you worry about with G6PD deficiency? What is the mechanism involved?

Answer 16

African Americans and Mediterranean regions;

oxidant drugs like anti-malarials deplete cell of reduced glutathione and lead to oxidative damage and hemolysis

Question 17

Favism?

Answer 17

G6PD deficient person consuming fava beans with oxidants can lead to severe hemolytic anemia

Question 18

Malignant hyperthermia: pattern of inheritance, cause, diagnosis

Answer 18

Autosomal dominant disease;
inhalation anesthetics with elevation of ionized calcium in the muscles leads to negative response (high fever, sustained contractions, hypercatabolism;
muscle biopsy and muscle contracture testing

Question 19

What does Cyp2C9 do with warfarin? What does warfarin do in general?

Answer 19

Degrades warfarin;

inhibits vitamin K epoxide reductase to prevent formation of reduced vitamin K

Question 20

If someone takes warfarin, what can increase the risk of bleeding? What can then reduce its effectiveness? What can change its effect?

Answer 20

1. Aspirin, ibuprofen, acetominophen
2. Foods like ginger and garlic;
3. Spinach, broccoli, brussel sprouts;
4. Alcohol