L12: Phase II metabolism

Question 1

What types of groups are acetylated during Phase II metabolism?

Answer 1

Amino (–NH₂), Hydroxyl (–OH), and Sulfhydryl (–SH) groups

Question 2

Which enzyme and cofactor are involved in acetylation?

Answer 2

Enzyme: Acetyltransferases (NAT1 and NAT2)
Cofactor: Acetyl-Coenzyme A (Acetyl-CoA)

Question 3

Where does acetylation occur within the cell?

Answer 3

In the cytosol

Question 4

What is required for a compound to undergo acetylation?

Answer 4

A free amine group

Question 5

What are NAT1 and NAT2 and where are they found?

Answer 5

NAT1: In most tissues; metabolises folate and sulfonamides
NAT2: In liver and intestine; metabolises drugs like isoniazid

Question 6

Which NAT is polymorphic and why is that important?

Answer 6

NAT2 is polymorphic → slow acetylators can have higher drug toxicity or altered efficacy

Question 7

What clinical condition first revealed NAT polymorphism?

Answer 7

Isoniazid toxicity in tuberculosis patients

Question 8

What effects can acetylation have on solubility and cancer risk?

Answer 8

Decreases solubility; may activate procarcinogens (e.g., aromatic amines in cooked meat)

Question 9

What does high NAT expression potentially increase the risk of?

Answer 9

Breast cancer via DNA adduct formation

Question 10

What is methylation in drug metabolism?

Answer 10

Addition of a methyl group (CH₃) to substrates

Question 11

What cofactor is needed for methylation?

Answer 11

S-adenosylmethionine (SAM)

Question 12

What is the main effect of methylation on drug molecules?

Answer 12

Increases lipophilicity and reduces biological activity

Question 13

Does methylation improve water solubility?

Answer 13

No

Question 14

Name the three classes of methyltransferases and their targets

Answer 14

O-methyltransferases: OH groups (e.g. catechol)
N-methyltransferases: NH₂ groups (e.g. histamine)
S-methyltransferases: SH groups (e.g. thiopurines)

Question 15

How is inorganic arsenic metabolised in the body?

Answer 15

Reduced by GSH, then methylated to MMA and DMA using SAM → excreted in urine

Question 16

What is glutathione (GSH) and its function?

Answer 16

A tripeptide antioxidant that maintains the cell’s reduced state

Question 17

What’s the active form of glutathione?

Answer 17

GSH (reduced form)

Question 18

What are Glutathione-S-Transferases (GSTs)?

Answer 18

Cytosolic enzymes (~25kDa) that detoxify electrophilic compounds using GSH

Question 19

What is formed during GST conjugation?

Answer 19

Mercapturic acid (excretable form)

Question 20

What subunits make up GSTs and where are they found?

Answer 20

Found in most tissues as homo- or heterodimers

Question 21

What are the GST subfamilies?

Answer 21

Alpha, Mu, Pi, and Theta

Question 22

Which GST subfamily is overexpressed in tumours?

Answer 22

GST Pi (not found in liver)

Question 23

Which GST subfamily is involved in paracetamol detoxification?

Answer 23

GST Pi conjugates NAPQI to non-toxic metabolites

Question 24

What happens if GSH is depleted during paracetamol metabolism?

Answer 24

NAPQI binds proteins → liver cell necrosis

Question 25

What types of drugs are conjugated by GSTs?

Answer 25

Cyclophosphamide, nitroglycerin, paracetamol, ethacrynic acid

Question 26

Which GST classes are inducible and what induces them?

Answer 26

Alpha and Mu; induced by PAHs, barbiturates, and antioxidants

Question 27

What are the effects of acetylation and methylation on solubility?

Answer 27

Neither improves solubility

Question 28

Which cofactor is used in acetylation vs methylation?

Answer 28

Acetylation: Acetyl-CoA Methylation: SAM

Question 29

Which types of groups can both acetylation and methylation modify?

Answer 29

NH₂, OH, SH groups

Question 30

Which of the following drugs is primarily metabolised by NAT2 and is affected by slow acetylator phenotype? A. Paracetamol B. Isoniazid C. Cyclophosphamide D. Ethacrynic acid

Answer 30

B

Question 31

Which statement about methylation is FALSE? A. It reduces water solubility. B. It uses SAM as a cofactor. C. It always increases biological activity. D. It increases lipophilicity.

Answer 31

C

Question 32

Which GST subfamily is associated with tumour tissues but not liver expression? A. Alpha B. Mu C. Pi D. Theta

Answer 32

C

Question 33

The detoxification of NAPQI into a non-toxic metabolite requires: A. Acetyl-CoA B. UDP-glucuronic acid C. GST Pi and GSH D. SULT1A1

Question 34

Which characteristic is unique to NAT2 compared to NAT1? A. Monomorphic gene expression B. Liver-specific expression C. Responsible for glucuronidation D. Uses UDP-glucuronic acid

Answer 34

B

Question 35

Which statement about glutathione is TRUE? A. It is a dipeptide made of glutamate and cysteine. B. It only detoxifies hydrophilic drugs. C. Its thiol group acts as a nucleophile. D. It requires acetyl-CoA for activation.

Answer 35

C

Question 36

Which of the following does not undergo metabolism via methylation? A. Catechol B. Thiopurines C. Histamine D. Sulfamethoxazole

Answer 36

D

Question 37

Which metabolic pathway is most likely to produce a DNA-reactive carcinogen from aromatic amines? A. Sulfation B. Glucuronidation C. Acetylation D. Methylation

Answer 37

C

Question 38

Why is glutathione important in arsenic metabolism? A. It activates arsenic for excretion. B. It reduces arsenate to arsenite. C. It acetylates arsenic to MMA. D. It methylates arsenic to DMA.

Answer 38

B

Question 39

Which pair correctly matches the enzyme with its class of substrates? A. SULT1A3 – SH groups B. GSTT1 – Small molecules C. O-methyltransferase – NH₂ groups D. NAT1 – DNA adducts

Answer 39

B