Lecture 14: Enzyme Inhibition & Its Importance in Drug Metabolism

Question 1

What is the effect of enzyme inhibition on drug metabolism?

Answer 1

It increases the level of the parent drug or active metabolites, leading to potential toxicity.

Question 2

Why is enzyme inhibition clinically important?

Answer 2

Because patients often take multiple drugs together, increasing the risk of drug-drug interactions via CYP450 inhibition.

Question 3

What is the role of CYP450 in drug metabolism?

Answer 3

It acts as a terminal oxidase in a mini electron transport chain, catalyzing oxidation using O₂.

Question 4

Describe the electron flow in CYP450 catalytic cycle.

Answer 4

NADPH donates electrons to CYP reductase, which transfers them to CYP450, enabling it to split O₂ and add an oxygen to the substrate.

Question 5

What happens to Km and Vmax in competitive inhibition?

Answer 5

Km increases; Vmax stays the same.

Question 6

What happens to Km and Vmax in uncompetitive inhibition?

Answer 6

Both Km and Vmax decrease.

Question 7

What happens to Km and Vmax in mixed inhibition?

Answer 7

Km increases and Vmax decreases.

Question 8

What happens to Km and Vmax in irreversible inhibition?

Answer 8

They effectively drop to zero due to permanent enzyme inactivation.

Question 9

What is a suicide substrate?

Answer 9

A substrate metabolised to a reactive intermediate which irreversibly inhibits the enzyme.

Question 10

Give examples of irreversible inhibitors of CYP3A4.

Answer 10

Erythromycin and Troleandomycin.

Question 11

What compound in grapefruit juice inhibits CYP3A4?

Answer 11

Furanocoumarins.

Question 12

What does disulfiram inhibit and what is the effect?

Answer 12

Aldehyde dehydrogenase; causes acetaldehyde buildup leading to nausea and flushing if alcohol is consumed.

Question 13

How does a Type I substrate affect CYP450?

Answer 13

Displaces H₂O from Fe³⁺, causing a high-spin (pentavalent) state; detected at 390 nm.

Question 14

How does a Type II substrate affect CYP450?

Answer 14

Binds in place of water, keeping Fe³⁺ in a low-spin (hexavalent) state; detected at 420 nm.

Question 15

Give examples of specific CYP inhibitors.

Answer 15

Furafylline (CYP1A2), Sulphaphenazole (CYP2C9), Quinidine (CYP2D6), Troleandomycin (CYP3A4).

Question 16

What is the role of inhibitory antibodies in CYP studies?

Answer 16

They block substrate access to specific isoforms, confirming their role in metabolism.

Question 17

What is the effect of CYP450 inhibition on drug levels in the body?

A. Increases metabolism of the parent drug
B. Reduces drug half-life
C. Increases parent drug and active metabolite levels
D. Enhances drug clearance

Answer 17

C

Question 18

Which cofactor is essential for CYP450 redox reactions?

A. FAD
B. NADPH
C. NADH only
D. ATP

Answer 18

B

Question 19

What happens to Vmax and Km during competitive inhibition?

A. Vmax decreases, Km stays the same
B. Vmax stays the same, Km increases
C. Vmax increases, Km decreases
D. Both Vmax and Km decrease

Answer 19

B

Question 20

Which of the following is an example of a suicide inhibitor of CYP3A4?

A. Quinidine
B. Sulphaphenazole
C. Troleandomycin
D. Terbinafine

Answer 20

C

Question 21

What is the mechanism of suicide inhibition?

A. Inhibitor binds reversibly to the active site
B. Substrate is metabolised to an active inhibitor
C. Inhibitor competes with oxygen for haem iron
D. The enzyme is protected from degradation

Answer 21

B

Question 22

Which of the following causes irreversible inhibition of CYP3A4 and can result in cardiac arrhythmia?

A. Disulfiram
B. Grapefruit juice
C. Ketoconazole
D. Quinidine

Answer 22

B

Question 23

Which feature is characteristic of non-competitive inhibition?

A. Inhibitor binds to the active site
B. Vmax is unchanged
C. Km decreases
D. Inhibitor binds an allosteric site

Answer 23

D

Question 24

What wavelength corresponds to a pentavalent CYP450 complex (when water is displaced)?

A. 420 nm
B. 340 nm
C. 450 nm
D. 390 nm

Answer 24

D

Question 25

Which drug is a competitive inhibitor of CYP2D6? A. Omeprazole B. Diazepam C. Quinidine D. Ketoconazole

Answer 25

C

Question 26

What structural group do most non-specific CYP inhibitors bind to? A. Phosphate group B. Protein backbone C. Haem prosthetic group D. Zinc-finger domain

Answer 26

C

Question 27

What is the main risk when two drugs are metabolised by the same CYP enzyme? A. Enhanced clearance B. Loss of pharmacological activity C. Accumulation and toxicity D. Faster therapeutic onset

Answer 27

C

Question 28

What is the peak wavelength for a reduced CYP450 bound to CO? A. 450 nm B. 420 nm C. 390 nm D. 310 nm

Answer 28

A

Question 29

What happens to Vmax and Km in uncompetitive inhibition? A. Vmax unchanged, Km increased B. Both Vmax and Km decrease C. Km unchanged, Vmax decreases D. Both Vmax and Km increase

Answer 29

B

Question 30

Which drug inhibits aldehyde dehydrogenase and is used in aversion therapy? A. Troleandomycin B. Disulfiram C. Erythromycin D. Furafylline

Answer 30

B

Question 31

What is the mechanism of action of ketoconazole on CYP450? A. Suicide inhibitor B. Non-competitive inhibitor C. Mixed inhibitor (binds haem) D. Uncompetitive inhibitor

Answer 31

C

Question 32

What is detected at 420 nm in CYP450 studies? A. Presence of reactive oxygen B. Resting Fe³⁺ state (hexavalent) C. Haem-oxygen complex D. NADPH binding

Answer 32

B

Question 33

Which inhibitor is used to confirm selective inhibition of CYP1A2? A. Disulfiram B. Ketoconazole C. Furafylline D. Quinidine

Answer 33

C

Question 34

What CYP is inhibited by omeprazole and diazepam (both substrates)? A. CYP1A2 B. CYP2C19 C. CYP3A4 D. CYP2D6

Answer 34

B

Question 35

What enzyme is inhibited in the metabolism of ethanol by disulfiram? A. Alcohol dehydrogenase B. Acetyl-CoA synthetase C. Aldehyde dehydrogenase D. CYP3A4

Answer 35

C

Question 36

What is a probe activity for CYP1A2 used in assays? A. N-demethylation of diazepam B. Methyl resorufin O-deethylation C. Oxidation of testosterone D. Sulphation of paracetamol

Answer 36

B