Pharmacology - CYP and Pharmacogenetics Lectures

Question 1

What is the main function of CYP enzymes?

Answer 1

They perform redox reactions

Question 2

T/F: Most CYP enzymes are found in the liver, but they also exist in the heart, kidney, lung and brain.

Answer 2

True

Question 3

Codeine is a prodrug that becomes what when metabolized?

Answer 3

Morphine (codeine is the substrate)

Question 4

What is induction?

Answer 4

Biotransformation by induced CYP enzymes results in either increased activity of prodrugs or enhanced elimination of drugs

Question 5

If a drug is inhibited, what happens to its bioavailability?

Answer 5

It increases, because the drug is not being metabolized.

Question 6

Polymorphism 2D6 is most commonly found in what population?

Answer 6

Ethiopians, 30%

Southern Europeans, 10%

Question 7

What CYP polymorphism is most commonly found in African Americans?

Answer 7

2C19

Also 15-20% in the Asian population

Question 8

40-55% of liver CYPs are what enzyme?

Answer 8

CYP 3A4

Question 9

CYP 2C9 is known to work on what substrates?

Answer 9

Warfarin

Phenytoin

Question 10

Rifampicin is a known inducer of what liver cytochrome enzymes?

Answer 10

2C9
2D6
Therefore, if a patient is taking rifampicin, it could have a negative effect on the amount of warfarin they’re also taking

Question 11

St. John’s wart is a known inducer of:

Answer 11

CYP 2C9
CYP 2C19
CYP 3A4
Therefore increased metabolism of drugs if taking St. John’s Wart

Question 12

Codeine is metabolized by:

Answer 12

CYP 2D6

Question 13

Give a known inhibitor: CYP1A2

Answer 13

Grapefruit juice

substrates like caffeine, theophyllin

Question 14

Give a known inhibitor: 2C9

Answer 14

Macrolide antibiotics

substrates like phenytoin, warfarin

Question 15

Give a known inhibitor: 2C19

Answer 15

Fluoxetine

substrates like diazepam

Question 16

Give a known inhibitor: 2D6

Answer 16

Quinidine

Substrates like codeine, haloperidol

Question 17

Give a known inhibitor: 3A4

Answer 17

Antifungals like ketoconazole, itraconazole

Substrates like terfenadine, verapimil

Question 18

Give a known inducer: 3A4

Answer 18

St. John’s Wort

Question 19

Give a known inducer: 2D6

Answer 19

Rifampicin

Question 20

Give a known inducer: 2C9

Answer 20

Rifampicin

Question 21

Give a known inducer: 1A2

Answer 21

smoking, charred food

Question 22

Polymorphisms exist for what CYPs?

Answer 22

2D6 (poor and extensive)
2C9 (poor)
2C19 (poor)

Question 23

2D6 polymorphisms are found in what percentage of white people?

Answer 23

5-10%

Question 24

Clopidogrel is used for:

Answer 24

Clopidogrel (Plavix®)
♦ Antiplateletagentusedtoinhibit blood clotting
♦ Coronary artery disease
♦ Vascular or cerebrovascular disease
♦ About 30% of patients fail to respond (CYP2C19 polymorphism)

Question 25

What chromosome is the allele for CYP2D6 found on?

Answer 25

22

Question 26

A ____metabolizer has no functional allele for the gene so is homozygous for one or more deleterious mutations.

Answer 26

A poor metabolizer has no functional allele for the gene so is homozygous for one or more deleterious mutations.

Question 27

An ____ metabolizer, on the other hand, has duplicate copies of the functional alleles resulting in increased enzyme activity.

Answer 27

An ultra metabolizer, on the other hand, has duplicate copies of the functional alleles resulting in increased enzyme activity.

Question 28

______ metabolizers are heterozygotes with one functional and one mutant allele which results in reduced enzyme activity.

Answer 28

Intermediate metabolizers are heterozygotes with one functional and one mutant allele which results in reduced enzyme activity.

Question 29

What are the most common loss of function alleles in the US?

Answer 29

TheCYP2C19 *2 (splice defect in exon 5) andCYP2C19 *3 (point mutation in exon 4) are the most common loss-of-function alleles in the US, accounting for 85% PMs (Caucasians) and 99% PMs (Asians).

• The CYP2C19 *17 gain-of-function allele (2 upstream single nucleotide polymorphisms -SNPs) results in increased enzymatic activity and is seen in approximately ~20-30% of European populations but only ~2-5% of Asian populations.

Question 30

G6PD deficiency is associated with what adverse drug reactions?

Answer 30

– susceptible to drug induced
hemolysis
• Oxidant drugs (e.g., primaquine) deplete the cell of reduced glutathione and lead to oxidative damage and hemolysis
Favism – oxidants in the fava bean can lead to severe hemolytic anemia in individuals with G6PD deficiency

Question 31

Studies have shown that there are two genes that directly affect warfarin metabolism.

Answer 31

• VKORC1 allele of the VKOR gene accounts for approximately 30% of the variation. There are low dose (more sensitive to the drug – common in Asians individuals) and high dose groups (more resistant so require higher dosage – common in African American).
• CYP2C9 allele of cytochrome p450 explains about 10% of variability. These polymorphisms are most common in Caucasian and rare in African Americans and Asians.