Lecture 12- Phase II metabolism 2

Question 1

what are the enzymes in acetylation?

Answer 1

NAT1 & NAT2 (acetyltransferase enzymes) - detected in human cytosol

Question 2

what donates the acetyl groups in acetylation ?

Answer 2

acetyl-CoA

Question 3

explain histroic 2 phases inactivations

Answer 3

1953
inactivation of isoniazid (TB drug) by NAT 2
fast acetylaters - break down quickly
slow- break down slowely (recessive)

1982
inactivation of arylamine dyes
- slow acetylator phenotype associated with bladder cancer

Question 4

where are both human NAT isoforms found and where is NAT 1 + 2 expressed?

Answer 4

isoforms - cytosol
NAT1 - mlost tissues
NAT 2- mainly liver and intestine
NOT INDUCIBLE

Question 5

Approx. ___% of the population unable to acetylate certain compounds
due to genetic polymorphism in NAT2

Answer 5

50

Question 6

NAT__ is sometimes referred to as the monomorphic NAT

Answer 6

NAT1 is sometimes referred to as the monomorphic NAT

Question 7

NAT enzymes onky work on drugs that have an ____ group

Answer 7

AMINO (-NH2)

NAT2 → Isoniazid (TB drug)
NAT1 → Sulfamethoxazole (antibiotic)

Question 8

give 3 effects of acetylation

Answer 8

1- masks amine group and can make some drugs less water soluble
2- can activate procarcinagens - some chems like aromatic arylamines can become more reactive and harmful- ^ cancer
3- acetylation is reversible for some drugs - some acetylated compounds can have acetyl group removed by esterase enzymes

Question 9

what is PhIP?

Answer 9

• aromatic arylamine (found in well cooked food)
• activated by NAT1 + 2
• high expression of NAT1+2 = increased breast cancer risk

Question 10

how does glutathione (GSH) work?

Answer 10

made of 3 amino acids (tripeptide)

• protects lipids from damage caused by free radicals
• high levels in liver (10mM) - important for detoxification

– can be oxidised (during glutathion peroxidase reaction to form oxidised form (GS-SG)

Question 11

what is role of GST?

Answer 11

conjugate - reduced glutathione to electrophilic compounds through nucleophilic cysteine thiol group

Question 11

what is GST (Glutathionje S-Transferase)

Answer 11

• mainly soluble enzymes found in cytosol
• consist of homo or hetrodimers of subunits of Mr approx 25,000
• found most human tissues
• large number of different isoforms

Question 12

what are the 4 different GST subfamilies found in humans ?

Answer 12

• Alpha class
  Mu
  Pi
  Theta

Question 13

what is the common genetic polimorphisms of GST?

Answer 13

-GSTT1 and GSTM1

Question 14

Which GST classes are inducible? and what induces them?

Answer 14

Alpha and mu
- polycyclic aromatic hydrocarbons
- barbiturates
- antioxidants

Question 15

___ induction thought to be protective against some
carcinogens

Answer 15

GST